Charney DS, Manji HK.
Life stress, genes, and depression:
multiple pathways lead to increased risk and new opportunities for intervention.
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]
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
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]
KS, Karkowski-Shuman L.
Stressful life events and genetic liability
to major depression: genetic control of exposure to the environment?
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]
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
Mol Psychiatry 1999 Mar;4(2):163-72
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
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
Psychol Med 2001 May;31(4):605-16
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]
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.
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."
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.
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."
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
"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."
KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
A longitudinal twin
study of 1-year prevalence of major depression in women.
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
Malignancy of recurrent, early-onset major depression: a family
Am J Med Genet 2001 Dec 8;105(8):690-9
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."
A, Gardner CO, Prescott CA, Cancro R, Kendler KS.
depression and gender: a population-based twin study.
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]
P, Katz R, Watkins S, Rutherford J.
A hospital-based twin register
of the heritability of DSM-IV unipolar depression.
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]
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.
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]
S, van Duijn CM, Baker FM, Launer L, Breteler MM, Schudel WJ, Hofman A.
study of familial aggregation of depression, dementia and Parkinson's disease.
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]
Major depression and generalised anxiety disorder. Same genes,
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."
KS, Neale MC, Kessler RC, Heath AC, Eaves LJ.
Major depression and
generalized anxiety disorder. Same genes, (partly) different environments?
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]
GN, Linkowski P, Delarbre C, Mendlewicz J.
Suicide on the paternal
and maternal sides of depressed patients with a lifetime history of attempted
Acta Psychiatr Scand 1991 Jun;83(6):417-9
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]
BS, Marazita ML, Zubenko WN, Spiker DG, Giles DE, Kaplan BB, Zubenko GS.
segregation analysis of recurrent, early-onset major depression: evidence for
single major locus transmission.
Am J Med Genet 2002 Mar
"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]
BS, Marazita ML, Zubenko WN, Kaplan BB, Zubenko GS.
analysis of alcohol and other substance-use disorders in families with recurrent,
early-onset major depression.
Am J Drug Alcohol Abuse 2002
"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]."
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]