unipolar depression heritability


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Charney DS, Manji HK.
Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention.
Sci STKE. 2004 Mar 16;2004(225):re5.
"Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing appreciation that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. The emerging evidence suggests that the combination of genetics, early life stress, and ongoing stress may ultimately determine individual responsiveness to stress and the vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to neurochemical alterations, but also to the impairments of cellular plasticity and resilience observed in depression. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell plasticity and resilience are long-term targets for the actions of antidepressant agents. Agents capable of reversing the hypothesized impairments of cellular resilience, reductions in brain volume, and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. Novel cellular targets include agents targeting neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput. The future development of treatments that more directly target molecules in critical CNS (central nervous system) signaling pathways that regulate cellular plasticity thus hold promise as novel, improved long-term treatments for major depression." [Abstract]

Kendler KS, Prescott CA.
A population-based twin study of lifetime major depression in men and women.
Arch Gen Psychiatry 1999 Jan;56(1):39-44
"BACKGROUND: Women report higher rates of major depression (MD) than men. Although genetic factors play an important etiologic role in MD, we are uncertain whether genetic factors are of equal importance in men and women, and whether the same genetic factors predispose men and women to MD. METHODS: We obtained, by telephone interview, a lifetime history of MD, defined by the DSM-III-R, from 3790 complete male-male, female-female, and male-female twin pairs, identified through a population-based registry. Results were analyzed using probandwise concordance, odds ratios, and biometrical twin modeling. RESULTS: The odds ratios (plus tetrachoric correlations) for lifetime MD were as follows: (1) male-male monozygotic, 3.29 (+0.37); (2) male-male dizygotic, 1.86 (+0.20); (3) female-female monozygotic, 3.02 (+0.39); (4) female-female dizygotic, 1.59 (+0.18); and (5) male-female dizygotic, 1.39 (+0.11). In the best-fitting twin model, the heritability of liability to MD was the same in men and women and equal to 39%, while the remaining 61% of the variance in liability was due to individual-specific environment. We rejected, with only modest confidence, the hypothesis that the genetic risk factors for MD were the same in men and women. The best-fitting model estimated the genetic correlation in the liability to MD in the 2 sexes to be +0.57. While we found no evidence to suggest a violation of the equal environment assumption, MD was less common in women from opposite-sex vs same-sex twin pairs. CONCLUSIONS: Major depression is equally heritable in men and women, and most genetic risk factors influence liability to MD similarly in the 2 sexes. However, genes may exist that act differently on the risk for MD in men vs women." [Abstract]

Kendler KS, Karkowski-Shuman L.
Stressful life events and genetic liability to major depression: genetic control of exposure to the environment?
Psychol Med 1997 May;27(3):539-47
"BACKGROUND: Although overwhelming evidence suggests that genetic and environmental risk factors both contribute to the aetiology of major depression (MD), we know little of how these two risk factor domains inter-relate. In particular, can the genetic liability to MD increase the risk of experiencing stressful life events (SLEs)? METHODS: Using discrete time survival analysis in a population-based sample of 2164 female twins, we examined whether the risks for nine personal and three aggregate network SLEs were predicted by the level of genetic liability to MD, indexed by the lifetime history of MD in monozygotic and dizygotic co-twins. RESULTS: Genetic liability to MD was associated with a significantly increased risk for six personal SLEs (assault, serious marital problems, divorce/breakup, job loss, serious illness and major financial problems) and one network SLE (trouble getting along with relatives/friends). This effect was not due to SLEs occurring during depressive episodes. Similar results were found using structural equation twin modelling. In contrast to the pattern observed with MD, the genetic liability to alcoholism impacted on the risk for being robbed and having trouble with the law. CONCLUSION: In women, genetic risk factors for MD increase the probability of experiencing SLEs in the interpersonal and occupational/financial domains. Genes can probably impact on the risk for psychiatric illness by causing individuals to select themselves into high risk environments." [Abstract]

Agid O, Shapira B, Zislin J, Ritsner M, Hanin B, Murad H, Troudart T, Bloch M, Heresco-Levy U, Lerer B.
Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia.
Mol Psychiatry 1999 Mar;4(2):163-72
"The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR=3.8, P=0.001). The effect of loss due to permanent separation (P=0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR=11.0, P=0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR=2.6, P=0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR=3.8, P=0.01), particularly before the age of 9 years (OR=4.3, P=0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n=136; BPD, n=107; SCZ, n=160), yielded few significant findings. Among the controls (n=170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P=0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress." [Abstract]

Kendler KS, Gardner CO, Neale MC, Prescott CA.
Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes?
Psychol Med 2001 May;31(4):605-16
"BACKGROUND: Although women are at consistently greater risk for major depression (MD) than men, it is unclear whether sex modifies the aetiological impact of genetic factors on MD. Is the heritability of MD different in men and women? Do the same genetic risk factors predispose to MD in the two sexes? METHODS: We obtained a lifetime history of MD by personal interview on two occasions from 6672 individual twins and 2974 complete twin pairs. Three diagnostic criteria of increasing narrowness were employed: DSM-III-R, DSM-III-R plus impairment and Washington University. To increase power by controlling for unreliability of assessment, we evaluated sex differences on genetic risk for MD using a structural equation measurement model. RESULTS: Using DSM-III-R criteria, but not the two narrower definitions, heritability of MD was significantly greater in women than in men. In the three diagnostic systems, the genetic correlation in liability to MD in men and women was estimated at between +0.50 and +0.65. These estimates differed significantly from unity for the two broader definitions. CONCLUSION: Using broad but not narrower definitions of illness, genetic factors play a greater role in the aetiology of MD in women than in men. The genes that influence risk for MD in the two sexes are correlated but are probably not entirely the same. These results raise the possibility that, in linkage and association studies, the impact of some loci on risk for MD will differ in men and women." [Abstract]

Gillespie NA, Kirk KM, Evans DM, Heath AC, Hickie IB, Martin NG.
Do the genetic or environmental determinants of anxiety and depression change with age? A longitudinal study of Australian twins.
Twin Res. 2004 Feb;7(1):39-53.
"Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the lifespan for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that midlife onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects." [Abstract]

Rice F, Harold GT, Thapar A.
Negative life events as an account of age-related differences in the genetic aetiology of depression in childhood and adolescence.
J Child Psychol Psychiatry. 2003 Oct;44(7):977-87.
"BACKGROUND: Many twin studies have reported that the genetic aetiology of depression differs according to age, with genetic influences being more important for adolescents than younger children. We sought to examine whether this age-related increase in the relative importance of genetic factors is due to an increase in gene-environment correlation specifically involving negative life events. METHOD: Questionnaires were sent to the families of a population-based sample of twins aged between 8 and 17 years. Parents of all the twins and adolescents aged 11 and over were asked to complete the Mood and Feelings Questionnaire (Costello & Angold, 1988) and a modified version of the Life Events Checklist (Johnson & McCutcheon, 1980). Responses were obtained from 1468 families and data were analysed using genetic model fitting. Bivariate analysis of 1) negative life events and 2) behaviour-dependent life events and depression symptoms was undertaken separately for children (aged 8 to 10 years) and adolescents (aged 11 to 17 years). Differences in genetic and environmental parameters across age groups were tested. RESULTS: Adolescence was associated with a greater number of behaviour-dependent life events. Genetic covariation of negative life events and depression was greater for adolescents than for children. CONCLUSIONS: Bivariate model fitting was consistent with the greater heritability of depression seen in adolescence being due to an increase in gene-environment correlation involving negative life events. However, the effects of genes associated specifically with maturation in adolescence, the possibility of 'person' effects and the role of other environmental factors also need to be considered." [Abstract]

Silberg J, Pickles A, Rutter M, Hewitt J, Simonoff E, Maes H, Carbonneau R, Murrelle L, Foley D, Eaves L.
The influence of genetic factors and life stress on depression among adolescent girls.
Arch Gen Psychiatry 1999 Mar;56(3):225-32
"BACKGROUND: The possible causes of greater depression among adolescent girls were investigated by examining variation in the influence of genetic and environmental risk factors among 182 prepubertal female, 237 prepubertal male, 314 pubertal female, and 171 pubertal male twin pairs from the Virginia Twin Study of Adolescent Behavioral Development. OBJECTIVES: To compare the trajectory of depressive symptoms among boys and girls from childhood to adolescence; to analyze the role of genetic, shared, and unique environmental factors in depression among prepubertal and pubertal male and female twins; and to investigate a possible link between liability to depression and one salient index of the child's environment: past-year life events. METHODS: Child-reported depression was assessed using the Child and Adolescent Psychiatric Interview and ratings of past-year life events and pubertal status obtained by maternal questionnaire and interview, respectively. RESULTS: The impact of life events on depression was particularly evident in the adolescent girls. The results from model fitting indicate increased heritability for depression in this group, and its long-term consistency was mediated primarily by latent genetic factors. Model fitting also showed that at least part of the liability to depression and to life events can be linked to a common set of genes in the adolescent girls, and there is a notable developmental increase in the genetic variance for life events. CONCLUSIONS: The greater heritability for depression in pubertal girls, its genetic mediation over time, and the increase in genetic variance for life events may be one possible explanation for the emergence of increased depression among pubertal girls and its persistence through adolescence." [Abstract]

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
A longitudinal twin study of 1-year prevalence of major depression in women.
Arch Gen Psychiatry 1993 Nov;50(11):843-52
"OBJECTIVES: This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. DESIGN: One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. PARTICIPANTS: Both members of 938 adult female-female twin pairs ascertained from the population-based Virginia Twin Registry. RESULTS: The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific environment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. CONCLUSIONS: These results suggest that: (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness." [Abstract]

Zubenko GS, Zubenko WN, Spiker DG, Giles DE, Kaplan BB.
Malignancy of recurrent, early-onset major depression: a family study.
Am J Med Genet 2001 Dec 8;105(8):690-9
"Coordinated efforts to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders are now underway. These studies have focused on recurrent, early-onset MDD (RE-MDD), the most heritable form of this disorder. The goal of this study was to characterize the burden of MDD and other mood disorders, comorbid mental disorders, and excess mortality in RE-MDD families. A total of 81 families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar MDD (RE-MDD), and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Approximately half of the first-degree relatives and a quarter of extended relatives of RE-MDD probands suffered from at least one mood disorder, typically MDD. As commonly observed for other oligogenic, multifactorial disorders, the severity of MDD reflected by age at onset and number of episodes attenuated with increasing familial/genetic distance from the proband. A substantial fraction of RE-MDD probands and their first-degree relatives met diagnostic criteria for additional psychiatric disorders that include prominent disturbances of mood. The deceased relatives of RE-MDD probands died at a median age that was 8 years earlier than for the local population; over 40% died before reaching age 65. These differences in mortality statistics resulted from a shift toward younger ages at death across the lifespan, including a fivefold increase in the proportion of individuals who died in the first year of life. Several-fold increases in the proportion of deaths by suicide, homicide, and liver disease were observed among the relatives of RE-MDD probands. However, the rank order of the three most common causes of death-heart disease, cancer, and stroke-remained unchanged and differences in the proportions of deaths from the remaining causes were small. RE-MDD is a strongly familial condition with a high rate of psychiatric comorbidity, whose malignant effects have a significant negative impact on the health and longevity of patients and their family members." [Abstract]

Fanous A, Gardner CO, Prescott CA, Cancro R, Kendler KS.
Neuroticism, major depression and gender: a population-based twin study.
Psychol Med 2002 May;32(4):719-28
"BACKGROUND: A portion of the genetic risk factors for the personality trait neuroticism (N) may also increase risk for major depression (MD). Females have both higher levels of N and higher rates of MD than males, suggesting that these traits may be more genetically correlated in females. METHODS: Structured interviews, including a lifetime assessment for MD by DSM-III-R criteria, were administered to 863 male-male MZ (monozygotic), 649 male-male DZ (dizygotic), 506 female-female MZ, 345 female-female DZ, and 1,408 opposite-sex twin pairs. N was assessed using the short-form of the Eysenck Personality Questionnaire. A sex-limited Cholesky model was fitted which allowed us to decompose into additive genetic, common environmental, and individual-specific environmental components two main classes of correlations: within-sex between-variable and between-sex within-variable. RESULTS: Our best-fitting model contained only additive genetic and individual-specific environmental factors for both N and MD. The within-sex genetic correlations between N and MD were estimated at +0.68 in men and +0.49 in women. This model fitted only slightly better than one in which the N-MD within-sex genetic correlation was constrained to be equal across the sexes, and estimated at +0.55. There may be sex-specific genes influencing both N and MD. CONCLUSION: Our best-fitting model failed to establish a significant sex difference in the genetic correlation between N and MD. These results, as well as evidence for sex-specific genetic factors for both traits, have implications for the diagnosis, classification, and treatment of the affective disorders, and molecular genetic approaches to the study of these traits." [Abstract]

McGuffin P, Katz R, Watkins S, Rutherford J.
A hospital-based twin register of the heritability of DSM-IV unipolar depression.
Arch Gen Psychiatry 1996 Feb;53(2):129-36
"OBJECTIVES: To estimate the contribution of genes and shared family environment to the liability to DSM-IV major depression and to examine the influence of certain proband characteristics on twin concordance. METHODS: We studied 177 probands with major depressive disorder ascertained via the Maudsley Hospital Twin Register (London, England) and their same-sex co-twins. Diagnostic assessments were carried out blind to zygosity and information on the other member of the twin pair. Probandwise concordances were used to compute correlations in liability, and model fitting was performed using maximum likelihood procedures. RESULTS: The probandwise concordance was 46% in monozygotic (n = 68) and 20% in dizygotic (n = 109) twins, a statistically highly significant difference. There was no evidence of a sex difference in heritability or of shared environmental effects. Depending on the assumed population risks for DSM-IV, major depression estimates of heritability were between 48% and 75%. A duration of longest episode of less than 13 months, multiple episodes, and an endogenous rather than neurotic pattern of symptoms as established by the International Classification of Diseases, Ninth Revision, in the proband were associated with a trend toward a higher monozygotic-dizygotic concordance ratio. Using log-linear analysis, only the association between duration of episodes and monozygotic-dizygotic concordance ratio was significant. CONCLUSIONS: Liability to DSM-IV major depression has a substantial heritable component, and there is no evidence of an effect of shared family environment. Some proband characteristics, especially shorter duration of episodes, may be associated with a larger degree of genetic determination." [Abstract]

Levinson DF, Zubenko GS, Crowe RR, DePaulo RJ, Scheftner WS, Weissman MM, Holmans P, Zubenko WN, Boutelle S, Murphy-Eberenz K, MacKinnon D, McInnis MG, Marta DH, Adams P, Sassoon S, Knowles JA, Thomas J, Chellis J.
Genetics of recurrent early-onset depression (GenRED): Design and preliminary clinical characteristics of a repository sample for genetic linkage studies.
Am J Med Genet 2003 May 15;119B(1):118-30
"This is an initial report on a six-site collaborative project, Genetics of Recurrent Early-Onset Depression (GenRED). This is a study of a large sample of families with recurrent major depressive disorder (DSM-IV) beginning by the age 30 in probands or 40 in relatives. Evidence suggests that early onset and recurrence of depressive episodes predict substantially increased risk of depression in first-degree relatives compared with the general population, suggesting that susceptibility genes might be mapped with this phenotype. The projected sample of 800-1,000 affected sibling pairs (ASPs) and other relatives will be studied using genome scan methods. Biological materials and blinded clinical data will be made available through the NIMH cell repository program. The sample should have good-to-excellent power to detect a locus associated with a 24% or greater population-wide increase in risk to siblings. We describe 838 affected individuals from the first 305 families containing 434 independent ASPs, or 613 ASPs counting all possible pairs. The mean age at the onset was 18.5 years, with a mean of 7.3 episodes and longest episode of 655 days. Almost all subjects had experienced at least 4 weeks of depression with five or more additional symptom criteria. Frequencies of symptoms and psychiatric and medical comorbid are provided. Substance use was more common in males, and panic disorder in females. Within pairs of affected siblings, correlations were significant for age at onset, substance abuse/dependence, panic disorder, obsessive-compulsive disorder and nicotine initiation and persistence. We replicated previously reported associations among comorbid panic disorder and social phobia, chronicity of depression and suicidal behavior. This suggests comparability of our cases to those in earlier large family studies. This dataset should prove useful for genetic studies of a highly familial form of major depressive disorder." [Abstract]

Fahim S, van Duijn CM, Baker FM, Launer L, Breteler MM, Schudel WJ, Hofman A.
A study of familial aggregation of depression, dementia and Parkinson's disease.
Eur J Epidemiol 1998 Apr;14(3):233-8
"Depression is often accompanied by other disorders including Alzheimer's disease and Parkinson's disease. We studied the familial aggregation of these disorders in order to examine the possibility of a shared genetic origin. In a population-based study of 6596 subjects, we studied the association of self-reported depression, which required treatment by a psychiatrist, to family history of psychiatric disease, dementia, and Parkinson's disease. A family history of psychiatric disease was significantly associated with overall depression as well as with unipolar (n = 303 patients) and bipolar (n = 27 patients) depression. The risk of unipolar depression was associated with the presence of two or more demented individuals among their first degree relatives (e.g. parents, siblings and children). Since there was no evidence for familial aggregation in subjects with only one demented relative, our study suggests that unipolar depression may be associated specifically to a strongly familial, form of dementia. The risk of bipolar depression was increased for those with one or more relatives with dementia and, perhaps, for those with relatives with Parkinson's disease. The familial aggregation of depression with dementia and perhaps Parkinson's disease suggests that there may be shared susceptibility gene(s) underlying these diseases. Our study indicates further that there may be differences in the genetic etiology between unipolar and bipolar depression." [Abstract]

Kendler KS.
Major depression and generalised anxiety disorder. Same genes, (partly)different environments--revisited.
Br J Psychiatry Suppl 1996 Jun;(30):68-75
"In both clinical and epidemiological samples, major depression (MD) and generalised anxiety disorder (GAD) display substantial comorbidity. In a prior analysis of lifetime MD and GAD in female twins, the same genetic factors were shown to influence the liability to MD and to GAD. A follow-up interview in the same twin cohort examined one-year prevalence for MD and GAD (diagnosed using a one-month minimum duration of illness). Bivariate twin models were fitted using the program Mx. High levels of comorbidity were observed between MD and GAD. The best-fitting twin models, when GAD was diagnosed with or without a diagnostic hierarchy, found a genetic correlation of unity between the two disorders. The correlation in environmental risk factors was +0.70 when GAD was diagnosed non-hierarchically, but zero when hierarchical diagnoses were used. Our findings provide further support for the hypothesis that in women, MD and GAD are the result of the same genetic factors. Environmental risk factors that predispose to 'pure' GAD episodes may be relatively distinct from those that increase risk for MD." [Abstract]

Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
Major depression and generalized anxiety disorder. Same genes, (partly) different environments?
Arch Gen Psychiatry 1992 Sep;49(9):716-22
"Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences." [Abstract]

Papadimitriou GN, Linkowski P, Delarbre C, Mendlewicz J.
Suicide on the paternal and maternal sides of depressed patients with a lifetime history of attempted suicide.
Acta Psychiatr Scand 1991 Jun;83(6):417-9
"The computational model of Slater, based on the analysis of ancestral secondary cases on the paternal and maternal sides of the subjects, was applied to depressed patients with a lifetime history of attempted suicide, either violent or nonviolent, in order to investigate possible modes of transmission of suicidal behavior. Among 549 patients, 15 had 2 or more ascendant first- and second-degree relatives who committed suicide. The results of the distribution of these cases were compatible with polygenic inheritance of suicidal behavior in depressed patients with a history of attempted suicide. In patients using violent methods, a significantly greater loading of ancestral secondary cases of suicide was observed on the maternal side and, in the nonviolent attempter group, on the paternal side." [Abstract]

Maher BS, Marazita ML, Zubenko WN, Spiker DG, Giles DE, Kaplan BB, Zubenko GS.
Genetic segregation analysis of recurrent, early-onset major depression: evidence for single major locus transmission.
Am J Med Genet 2002 Mar 8;114(2):214-21
"Coordinated efforts are now underway to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders. These studies have focused on recurrent, early-onset MDD (RE-MDD), thought to be the most familial form of this disorder. The goal of this study was to conduct a complex segregation analysis of recurrent MDD and other major mood disorders aggregating in families identified by probands with RE-MDD. Eighty-one families were identified through probands over the age of 18 who met criteria for recurrent (> or =2 episodes), early-onset (< or =25 years), nonpsychotic, unipolar MDD (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best-estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. The segregation analysis of recurrent MDD supported a sex-independent Mendelian codominant model. Analysis of major mood disorders supported a sex-independent Mendelian dominant model. Interestingly, inclusion of spousal residual correlations provided better fitting models for recurrent MDD but not the broader phenotype of major mood disorders. Unlike unipolar MDD, the lifetime prevalence of bipolar I disorder in this sample of families did not exceed the reported population prevalence [Zubenko et al., 2001]. Our results suggest that a major locus contributes to the expression of recurrent MDD and possibly other major mood disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). The absence of aggregation of bipolar I disorder in these families strongly suggests that while the genetic determinants of unipolar and bipolar disorders may overlap, they are not identical. Our findings illustrate the advantage of employing families identified by probands with RE-MDD in studies designed to detect susceptibility loci for unipolar MDD and related disorders." [Abstract]

Maher BS, Marazita ML, Zubenko WN, Kaplan BB, Zubenko GS.
Genetic segregation analysis of alcohol and other substance-use disorders in families with recurrent, early-onset major depression.
Am J Drug Alcohol Abuse 2002 Nov;28(4):711-31
"OBJECTIVE: The goal of this study was to conduct a complex segregation analysis of alcohol and other substance-use disorders in families identified by probands with recurrent, early-onset major depression (RE-MDD). METHOD: Eighty-one families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar major depression (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. RESULTS: The best-fitting models for the transmission of "alcohol use disorders" or "alcohol/other substance use disorders" were sex-dependent Mendelian recessive models with significant residual spousal effects. Moreover, the parameter estimates for the models were very similar for these phenotypes. In contrast, the segregation analysis of "substance use disorder" supported a transmissible, but non-Mendelian, major effect. CONCLUSIONS: Our results suggest that a major locus contributes to the expression of alcohol use disorders or alcohol/other substance-use disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). Previous studies supported single gene transmission of recurrent major depression and major mood disorders in these families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002. 114 (2), 214-221]. Mounting evidence suggests that at.least some of this "comorbidity" may result from the effects of shared susceptibility genes or an overlap in the sets of genes that contribute to the vulnerability of developing these mental disorders [Zubenko, G.S. Mol. Psychiatry 2000, 5, 131-136]." [Abstract]

Farmer A, Breen G, Brewster S, Craddock N, Gill M, Korszun A, Maier W, Middleton L, Mors O, Owen M, Perry J, Preisig M, Rietschel M, Reich T, Jones L, Jones I, McGuffin P
The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study.
BMC Psychiatry. 2004 Dec 9;4(1):42.
BACKGROUND: The Depression Network Study (DeNt) is a multicentre study designed to identify genes and/or loci linked to and/or associated with susceptibility to unipolar depression in Caucasian families. This study presents the method and socio-demographic details of the first 470 affected sibling pairs recruited from 8 different sites in Europe and the United States of America. METHODS: Probands fulfilling either the Diagnostic and Statistical Manual 4th edition (DSM-IV) or the International Classification of Diseases 10th edition (ICD-10) criteria for recurrent unipolar depression of moderate or severe degree and who had at least one similarly affected sibling were eligible for the study. Detailed clinical and psychological assessments were undertaken on all subjects including an interview using the Schedules for Clinical Assessment in Neuropsychiatry. Blood samples were collected from all participants to extract DNA for linkage analysis. RESULTS: The different sites used different recruitment strategies depending on local health care organisation but despite this there was remarkable similarity across sites for the subjects recruited. Although the Bonn site had significantly older subjects both for age of onset and age at interview, for the sample as a whole, subjects were interviewed in their mid-40s and had experienced the onset of their recurrent depression in their 20s. Preliminary genome screening was able to include 929 out of the 944 subjects (98.4%) typed at 932 autosomal and 544 X chromosome markers. CONCLUSIONS: This paper describes the methodology and the characteristics of the subjects from the 414 families included in the first wave of genotyping from the multi-site DeNT study. Ultimately the study aims to collect affected sibling pairs from approximately 1200 families. [Abstract]


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Recent Unipolar Depression Genetic Research

1) Brown GW, Ban M, Craig TK, Harris TO, Herbert J, Uher R
Depress Anxiety. 2012 Jul 27;
BACKGROUND: Key questions about the interaction between the serotonin transporter length polymorphism (5-HTTLPR) and stress in the etiology of depression remain unresolved. We test the hypotheses that the interaction is restricted to childhood maltreatment (as opposed to stressful events in adulthood), and leads to chronic depressive episodes (as opposed to any onset of depression), using gold-standard assessments of childhood maltreatment, severe life events, chronic depression, and new depressive onsets. METHOD: In a risk-enriched sample of 273 unrelated women, childhood maltreatment was retrospectively assessed with the Childhood Experience of Care and Abuse (CECA) interview and 5-HTTLPR was genotyped. A subset of 220 women was followed prospectively for 12 months with life events assessed with the Life Events and Difficulties (LEDS) interview. Any chronic episode of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. RESULTS: The short alleles of 5-HTTLPR moderated the relationship between childhood maltreatment and chronic depression in adulthood, reflected in a significant gene-environment interaction (RD = 0.226, 95% CI: 0.076-0.376, P = .0032). 5-HTTLPR did not moderate the effects of either childhood maltreatment or severe life events on new depressive onsets. CONCLUSIONS: The short variant of the serotonin transporter gene specifically sensitizes to the effect of early-life experience of abuse or neglect on whether an adult depressive episode takes a chronic course. This interaction may be responsible for a substantial proportion of cases of chronic depression in the general population. Depression and Anxiety 00:1-9, 2012. © 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

2) Herbert J, Ban M, Brown GW, Harris TO, Ogilvie A, Uher R, Craig TK
Interaction between the BDNF gene Val/66/Met polymorphism and morning cortisol levels as a predictor of depression in adult women.
Br J Psychiatry. 2012 Jul 26;
BACKGROUND: Common genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression. AIMS: To determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women. METHOD: We recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva. RESULTS: There were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels. CONCLUSIONS: Morning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression. [PubMed Citation] [Order full text from Infotrieve]

3) Fisher HL, Cohen-Woods S, Hosang GM, Korszun A, Owen M, Craddock N, Craig IW, Farmer AE, McGuffin P, Uher R
Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder.
J Affect Disord. 2012 Jul 25;
BACKGROUND: There is inconsistent evidence of interaction between stressful events and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. Recent studies have indicated that the moderating effect of 5-HTTLPR may be strongest when adverse experiences have occurred in childhood and the depressive symptoms persist over time. However, it is unknown whether this gene-environment interaction is present for recurrent depressive disorder and different forms of maltreatment. Therefore, patients with recurrent clinically diagnosed depression and controls screened for the absence of depression were utilised to examine the moderating effect of 5-HTTLPR on associations between specific forms of childhood adversity and recurrent depression. METHOD: A sample of 227 recurrent unipolar depression cases and 228 never psychiatrically ill controls completed the Childhood Trauma Questionnaire to assess exposure to sexual, physical and emotional abuse, physical and emotional neglect in childhood. DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS: All forms of childhood maltreatment were reported as more severe by cases than controls. There was no direct association between 5-HTTLPR and depression. Significant interactions with additive and recessive 5-HTTLPR genetic models were found for overall severity of maltreatment, sexual abuse and to a lesser degree for physical neglect, but not other maltreatment types. LIMITATIONS: The cross-sectional design limits causal inference. Retrospective report of childhood adversity may have reduced the accuracy of the findings. CONCLUSIONS: This study provides support for the role of interplay between 5-HTTLPR and a specific early environmental risk in recurrent depressive disorder. [PubMed Citation] [Order full text from Infotrieve]

4) Edgar N, Sibille E
A putative functional role for oligodendrocytes in mood regulation.
Transl Psychiatry. 2012 Feb 21;2:e109.
Altered glial structure and function is implicated in several major mental illnesses and increasing evidence specifically links changes in oligodendrocytes with disrupted mood regulation. Low density and reduced expression of oligodendrocyte-specific gene transcripts in postmortem human subjects points toward decreased oligodendrocyte function in most of the major mental illnesses. Similar features are observed in rodent models of stress-induced depressive-like phenotypes, such as the unpredictable chronic mild stress and chronic corticosterone exposure, suggesting an effect downstream from stress. However, whether oligodendrocyte changes are a causal component of psychiatric phenotypes is not known. Traditional views that identify oligodendrocytes solely as nonfunctional support cells are being challenged, and recent studies suggest a more dynamic role for oligodendrocytes in neuronal functioning than previously considered, with the region adjacent to the node of Ranvier (i.e., paranode) considered a critical region of glial-neuronal interaction. Here, we briefly review the current knowledge regarding oligodendrocyte disruptions in psychiatric disorders and related animal models, with a focus on major depression. We then highlight several rodent studies, which suggest that alterations in oligodendrocyte structure and function can produce behavioral changes that are informative of mood regulatory mechanisms. Together, these studies suggest a model, whereby impaired oligodendrocyte and possibly paranode structure and function can impact neural circuitry, leading to downstream effects related to emotionality in rodents, and potentially to mood regulation in human psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

5) Woudstra S, Bochdanovits Z, van Tol MJ, Veltman DJ, Zitman FG, van Buchem MA, van der Wee NJ, Opmeer EM, Demenescu LR, Aleman A, Penninx BW, Hoogendijk WJ
Piccolo genotype modulates neural correlates of emotion processing but not executive functioning.
Transl Psychiatry. 2012 Feb 21;2:e99.
Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene-involved in monoaminergic neurotransmission-as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD. [PubMed Citation] [Order full text from Infotrieve]

6) Frodl T, Carballedo A, Hughes MM, Saleh K, Fagan A, Skokauskas N, McLoughlin DM, Meaney J, O'Keane V, Connor TJ
Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.
Transl Psychiatry. 2012 Feb 21;2:e88.
Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response. [PubMed Citation] [Order full text from Infotrieve]

7) Singh YS, Altieri SC, Gilman TL, Michael HM, Tomlinson ID, Rosenthal SJ, Swain GM, Murphey-Corb MA, Ferrell RE, Andrews AM
Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells.
Transl Psychiatry. 2012 Feb 21;2:e77.
The human serotonin transporter (SERT) gene possesses a 43-base pair (bp) insertion-deletion promoter polymorphism, the h5-HTTLPR. Genotype at this locus correlates with variation in anxiety-related personality traits and risk for major depressive disorder in many studies. Yet, the complex effects of the h5-HTTLPR, in combination with closely associated single-nucleotide polymorphisms (SNPs), continue to be debated. Moreover, although SERT is of high clinical significance, transporter function in vivo remains difficult to assess. Rhesus express a promoter polymorphism related to the h5-HTTLPR. The rh5-HTTLPR has been linked to differences in stress-related behavior and cognitive flexibility, although allelic variations in serotonin uptake have not been investigated. We studied the serotonin system as it relates to the 5-HTTLPR in rhesus peripheral blood cells. Sequencing of the rh5-HTTLPR revealed a 23-bp insertion, which is somewhat longer than originally reported. Consistent with previous reports, no SNPs in the rh5-HTTLPR and surrounding genomic regions were detected in the individuals studied. Reductions in serotonin uptake rates, cell surface SERT binding, and 5-hydroxyindoleacetic acid/serotonin ratios, but not SERT mRNA levels, were associated with the rh5-HTTLPR short allele. Thus, serotonin uptake rates are differentiable with respect to the 5-HTTLPR in an easily accessible native peripheral tissue. In light of these findings, we foresee that primary blood cells, in combination with high sensitivity functional measurements enabled by chronoamperometry, will be important for investigating alterations in serotonin uptake associated with genetic variability and antidepressant responsiveness in humans. [PubMed Citation] [Order full text from Infotrieve]

8) Mitjans M, Gastó C, Catalán R, Fañanás L, Arias B
Genetic variability in the endocannabinoid system and 12-week clinical response to citalopram treatment: the role of the CNR1, CNR2 and FAAH genes.
J Psychopharmacol. 2012 Jul 23;
First line treatment of major depression is based on selective serotonin re-uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment. [PubMed Citation] [Order full text from Infotrieve]

9) Albert PR
Transcriptional regulation of the 5-HT1A receptor: implications for mental illness.
Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2402-15.
The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene × environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5-HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression. [PubMed Citation] [Order full text from Infotrieve]

10) Jia P, Kao CF, Kuo PH, Zhao Z
A comprehensive network and pathway analysis of candidate genes in major depressive disorder.
BMC Syst Biol. 2011 Dec 23;5 Suppl 3:S12.
[PubMed Citation] [Order full text from Infotrieve]

11) Zill P, Baghai TC, Schüle C, Born C, Früstück C, Büttner A, Eisenmenger W, Varallo-Bedarida G, Rupprecht R, Möller HJ, Bondy B
DNA Methylation Analysis of the Angiotensin Converting Enzyme (ACE) Gene in Major Depression.
PLoS One. 2012;7(7):e40479.
[PubMed Citation] [Order full text from Infotrieve]

12) Vyas NS, Puri BK
Evidence for an Association between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and General Intellectual Ability in Early-Onset Schizophrenia.
Isr J Psychiatry Relat Sci. 2012;49(2):137-42.
Background: Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, development and maintenance of neuronal systems, and the Val66Met polymorphism has been implicated in memory functions. Method: We examined the association of BDNF with general intellectual ability in 161 individuals including 53 early-onset patients with schizophrenia (EOS), 91 healthy biological relatives, and 17 relatives with major depressive disorder (MDD), using the Wechsler Intelligence Scales (WISC). Results: Regardless of diagnosis, individuals with the Met66 allele had a significantly higher performance score than those homozygous for Val66 on vocabulary, block design and object assembly subtests of the WISC. EOS probands showed poor performance on all IQ subtests compared with relatives with and without MDD. Limitations: Relatively smaller sample size of individual genotypes. Conclusions: BDNF genotype may play a role in specific cognitive functions and dimensions of intelligence. The Met allele appears to be associated with superior performance in IQ compared with relatives Val/Val genotype. [PubMed Citation] [Order full text from Infotrieve]

13) Bader V, Tomppo L, Trossbach SV, Bradshaw NJ, Prikulis I, Leliveld SR, Lin CY, Ishizuka K, Sawa A, Ramos A, Rosa I, García A, Requena JR, Hipolito M, Rai N, Nwulia E, Henning U, Ferrea S, Luckhaus C, Ekelund J, Veijola J, Järvelin MR, Hennah W, Korth C
Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
Hum Mol Genet. 2012 Jul 13;
Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated association of physical and social anhedonia with the CRMP1 locus in a DISC1-dependent manner. Physical and social anhedonia are heritable traits, present as chronic negative symptoms of schizophrenia and severe major depression thus constituting a serious vulnerability factor for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role of a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of disease-associated epitope in post mortem brains, powered by a genetic association study is rapidly translated into a potential blood-based diagnostic marker. [PubMed Citation] [Order full text from Infotrieve]

14) Wang Y, Liu X, Yu Y, Han Y, Wei J, Collier D, Li T, Ma X
The role of single nucleotide polymorphism of D(2) dopamine receptor gene on major depressive disorder and response to antidepressant treatment.
Psychiatry Res. 2012 Jul 13;
The study analyzed the effect of dopamine 2 receptor gene (DRD2) polymorphism on the risk for major depressive disorder (MDD) and the response to selective serotonin reuptake inhibitors (SSRIs). The results suggest that the DRD2 gene may play a role on MDD susceptibility and the onset-time of antidepressant response. [PubMed Citation] [Order full text from Infotrieve]

15) Yang Z, Ma X, Wang Y, Wang J, Xiang B, Wu J, Deng W, Li M, Wang Q, Li T
Association of APC and REEP5 gene polymorphisms with major depression disorder and treatment response to antidepressants in a Han Chinese population.
Gen Hosp Psychiatry. 2012 Jul 12;
OBJECTIVE: Despite the high prevalence of depression and its considerable impact on the population, knowledge about the pathogenesis of the illness and the antidepressant treatment response is still unknown. METHODS: A total of 397 patients with major depression disorder (MDD) and 473 normal controls were employed in the present research. Twelve single nucleotide polymorphisms (SNPs) within the adenomatous polyposis coli (APC) and receptor accessory protein (REEP5) genes were selected for genotyping using the GoldenGate genotyping assay. A total of 165 MDD patients completed a 6-week antidepressant treatment. Responders were defined as patients with at least a 50% reduction in Hamilton Rating Scale for Depression total scores posttreatment. RESULTS: Two SNPs (rs2464805 and rs563556) within the APC gene exhibited a statistically significant association with MDD when analyzed by genotype and allele frequencies. Three SNPs (rs495794, rs153549 and rs153560) in the REEP5 gene showed significant statistical differences between the responders and nonresponders. CONCLUSIONS: The APC gene may be one of the susceptibility genes for MDD as well as a genetic link between psychiatric disease and cancer. REEP5 gene polymorphisms may influence antidepressant treatment response in MDD. [PubMed Citation] [Order full text from Infotrieve]

16) Blazquez A, Mas S, Plana MT, Lafuente A, Lázaro L
Fluoxetine pharmacogenetics in child and adult populations.
Eur Child Adolesc Psychiatry. 2012 Jul 12;
Although fluoxetine is useful in the treatment of major depression, 30-40 % of the patients do not respond to therapy. The response seems to be influenced by certain genes which are involved in the drug's pharmacodynamics and pharmacokinetics. The present study reviews the literature on genetic contributions to fluoxetine response in children and adults, and concludes that the different polymorphisms of CYP2D6 and CYP2C9 may influence the blood concentrations of fluoxetine. If the childhood dose is adjusted for weight, differences between children and adults are unlikely. As regards the genes that influence the drug's pharmacodynamics, polymorphisms of SLC6A4, HTR1A and MAO-A seem to be involved in the response to fluoxetine, while the genes COMT, CRHR1, PDEA1, PDEA11 GSK3B and serpin-1 also seem to play a role. Comparison of different studies reveals that the results are not always consistent, probably due to methodological differences. Other factors such as gender or ethnicity may also influence treatment response. [PubMed Citation] [Order full text from Infotrieve]

17) Mischoulon D, Lamon-Fava S, Selhub J, Katz J, Papakostas GI, Iosifescu DV, Yeung AS, Dording CM, Farabaugh AH, Clain AJ, Baer L, Alpert JE, Nierenberg AA, Fava M
Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment.
CNS Spectr. 2012 Jun;17(2):76-86.
[PubMed Citation] [Order full text from Infotrieve]

18) Lagus M, Gass N, Saharinen J, Savelyev S, Porkka-Heiskanen T, Paunio T
Inter-tissue Networks Between the Basal Forebrain, Hippocampus, and Prefrontal Cortex in a Model for Depression Caused by Disturbed Sleep.
J Neurogenet. 2012 Jul 11;
Disturbances in sleep are encountered in the majority of patients with depressive disorder. To elucidate the molecular mechanisms behind this relationship, we examined gene expression changes in a rodent model for disturbed sleep and depression. The animals were treated with daily injections of clomipramine to affect their sleep during early infancy. This early interference with sleep is known to induce depression-like behavior in adult animals. After 2 weeks of treatment, the change in gene expression was examined using the Affymetrix Rat 230.2 chip. We studied the gene expression in the basal forebrain, hippocampus, and frontal cortex and combined the results to reveal the otherwise indissectible networks between and around the tissues. The major disrupted pathways between the three brain areas were related to synaptic transmission, regulation of translation, and ubiquitinylation. The involved pathways were within the cellular components of the axons, growth cones, melanosomes, and pigment granules. A network analysis allowing for additional interactors, in the form of chemicals or gene products, revealed a disturbed communicational network between the different brain areas. This disturbed network is centered around serotonin, Mn(II), and Rhoa. The findings elucidate inter-tissue pathways and networks in the brain that are involved in sleep and mood regulation. The findings are of uttermost interest, some are quite predictable and obvious, but some are novel or have only been proposed by rare theoretical speculations (such as the melanosome and Mn(II) involvement). Equally important as the findings are the methods described in this article. In this study, we present two novel simple ways to perform system biological analysis based on gene expression array data. We used two already existing tools in a new way, and by careful planning of the input data, managed to extrapolate intricate hidden inter-tissue networks to build a molecular picture of disease. [PubMed Citation] [Order full text from Infotrieve]

19) Dunlop BW, Binder EB, Cubells JF, Goodman MG, Kelley ME, Kinkead B, Kutner M, Nemeroff CB, Newport DJ, Owens MJ, Pace TW, Ritchie JC, Aponte Rivera V, Westen D, Craighead WE, Mayberg HS
Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT): Study Protocol for a Randomized Controlled Trial.
Trials. 2012 Jul 9;13(1):106.
ABSTRACT: BACKGROUND: Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient's treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition. METHODS: Treatment-naive adults aged 18-65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: 1) cognitive behavior therapy (CBT, 16 sessions), 2) duloxetine (30-60 mg/d), or 3) escitalopram (10-20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occur at an early time-point in treatment, and upon completion of 12-week treatment, when a a second Dex/CRH test is also conducted, Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes. DISCUSSION: The PReDICT study's evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness. [PubMed Citation] [Order full text from Infotrieve]

20) Kishi T, Ichinose H, Yoshimura R, Fukuo Y, Kitajima T, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Musso GM, Umene-Nakano W, Nakamura J, Ozaki N, Iwata N
GTP cyclohydrolase 1 gene haplotypes as predictors of SSRI response in Japanese patients with major depressive disorder.
J Affect Disord. 2012 Jul 5;
BACKGROUND: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). METHOD: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. RESULT: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). CONCLUSIONS: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small. [PubMed Citation] [Order full text from Infotrieve]