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John M. Hettema, M.D., Ph.D.

Genetics of Depression
Abstract: Depressive disorders are commonly occurring psychiatric conditions that tend to run in families. They are
heterogeneous and complex, predicted to involve the interplay between multiple genes and nongenetic risk factors, such
as stressful life events. Their phenomenology and biological substrates are not clearly distinguished from those of
normal mood states on the one hand and frequently comorbid conditions such as the anxiety disorders on the other,
further complicating research into their etiology. Preliminary molecular genetic studies performed over the past several
decades have implicated only a modest number of specic candidate genes in major depression, thus far offering
little insight into its pathophysiological basis. This leaves open the way for a new wave of large-scale, genome-wide
association studies that are providing vastly increased amounts of preliminary data for understanding these important
conditions.
Major depressive disorder (MDD) occurs com-
monly in the general population. Cross-sectional
epidemiological surveys that systematically screen
for psychiatric disorders in unselected, representa-
tive samples nd that approximately 7% of U.S.
adults had experienced an episode of MDD some-
time in the 12 months before the interview (1).
Using retrospective assessment, such surveys esti-
mate that 16% of adults have experienced a major
depressive episode during their lifetime; longitudi-
nal studies suggest that cumulative lifetime preva-
lence rates may be higher still (2, 3). Recurrent
MDD, i.e., a condition in which individuals expe-
rience multiple clinically signicant depressive ep-
isodes over the course of their life, occurs in about
one-third to two-thirds of these individuals (4); as
discussed below, this subtype may have more rele-
vance for genetics. Because of the high prevalence
of MDD in countries around the world and the
substantial impairment with which it is associated,
the World Health Organization has predicted that
it would rank second to ischemic heart disease in
global burden of disease by 2020 (5). Therefore,
understanding its etiological and pathophysiologi-
cal basis is critical.
This article will review and summarize the extant
research regarding the genetics of major depressive
disorder. The term disorder emphasizes the focus
on clinically dened depressive conditions such as
MDD rather than a vaguely dened state of de-
pression. Some have reasonably argued that the
nosological denitions for psychiatric diagnoses, al-
though designed and useful for making clinical as-
signments and treatment decisions, do not neces-
sarily provide an optimumbasis for genetic or other
biological lines of inquiry. For example, the precise
thresholds requiring a 2-week duration or ve of
nine associated symptoms for DSM-IVdiagnosis of
MDD do not seem to represent a genetically dis-
tinct condition (6). Nor can we answer the deeper
question, with its philosophical and pragmatic im-
plications, as to whether depressive illness is cat-
egorically different from states of normal sadness
(as is assumed in the medical model) or simply a
more severe manifestation of it on the same contin-
uum of affect. This sort of question has arguably
more relevance for depressive disorders than for,
say, schizophrenia. If, as the medical model as-
sumes, there are disease genes that have specic
dysfunction in MDD, then the procedure is to de-
tect these using the classic case-control design, test-
ing for differences in the structure or function of
specic genes between those who are affected with
and those who are free from the disorder. On the
other hand, if the mechanisms underlying normal
variation in mood are the same as those that cause
affective illness, then one could simply study the
former in a general population sample to identify
the genetic mechanisms underlying MDD. This
approach has clear parallels to the study of other
common medical conditions such as hypertension
and diabetes and their relationship to physiological
regulation of blood pressure and glucose homeosta-
sis, respectively. Because of the absence of knowl-
CME Disclosure
John M. (Jack) Hettema, M.D., Ph.D., Associate Professor of Psychiatry, Virginia Institute for
Psychiatric and Behavioral Genetics, Virginia Commonwealth University, attending physician VCU
Anxiety Disorders Specialty Clinic.
Reports no nancial relationships with commercial interests.
Address correspondence to John M. Hettema, M.D., Ph.D., Department of Psychiatry, Virginia
Institute for Psychiatric and Behavioral Genetics, P.O. Box 980126, Richmond, Virginia 23298-
0126; e-mail: jhettema@vcu.edu.
Summer 2010, Vol. VIII, No. 3 F O C U S THE J OURNAL OF LI FELONG LEARNI NG I N PS YCHI ATRY
316
edge of these fundamental features of the entity of
clinical depression, I will limit this reviewto studies
that examine the syndrome of MDD, for lack of a
better current model.
GENETIC EPIDEMIOLOGICAL STUDIES
OF MDD
The usual sequence of establishing the genetic
basis of a condition goes from (1) family studies to
establish its familial aggregation, to (2) twin and
adoption studies to distinguish genetic versus fam-
ily environmental sources of aggregation, and then
to (3) molecular genetic studies to identify specic
susceptibility loci and their functional role in pro-
ducing the condition. Family studies compare rates
of illness in relatives of those who have the condi-
tion (case probands) with rates in relatives of
healthy control subjects. Higher rates in the former
group of relatives suggest familial aggregation; i.e.,
there is an association of illness in probands with
illness in their relatives. A systematic meta-analysis
that included ve well-done family studies of
MDD reported a summary odds ratio of 2.84, i.e.,
individuals biologically related to someone with
MDD have almost three times the risk of MDD
compared with those without a family history of the
disorder (7). To put this statistic into perspective,
relatives of patients with schizophrenia have about
a 10-fold risk of developing that condition com-
pared with the general population. Both of these are
similar to familiar risk estimates for common med-
ical conditions such as type II diabetes but far
smaller than those for a Mendelian disorder such as
Huntingtons disease.
Twin studies allow one to separate genetic from
environmental inuences by comparing resem-
blance for the condition within two types of twin
pairs: monozygotic twins, who share 100% of their
DNA, and dizygotic twins, who share, on average,
50% of their DNA like other sibling pairs. Greater
monozygotic than dizygotic resemblance for the
condition suggests at least a partial genetic basis.
This is quantied by estimating the heritability, the
portion of individual differences due to genetic ef-
fects. [See Neale and Cardon (8) for more details on
twin study methodology.] The meta-analysis cited
above includes data from ve well-done twin stud-
ies of MDD and reports a summary heritability of
37% (7). One large twin study that used longitudi-
nal data to reduce measurement error estimated the
reliability-adjusted heritability to be 66% (9).
These results suggest that the effects of genes ac-
count for one-third to two-thirds of liability to
MDD, with the remaining portion of risk due to
environmental inuences. For the latter, childhood
adversity and recent stressful life events are rmly
established risk factors in MDD [see, for example,
Paykel (10) and Kessler (11)].
FACTORS AFFECTING GENETIC RISK OF MDD
Several modiers of MDDgenetic risk have been
identied [reviewed in detail by Levinson (12)].
Recurrent MDDhas been shown in some studies to
have greater familial risk; thus, having a single de-
pressive episode sometime in ones lifetime may
have less to do with genetics than does MDD that
recurs. Similarly, for age of onset: more familial
forms of the disorder may manifest earlier in life.
For these reasons, some molecular genetic research-
ers seeking to identify depression susceptibility
genes have focused their efforts on the phenotype of
recurrent, early-onset MDD. Female gender, on
the other hand, although an important indepen-
dent risk factor for MDD (13), has not been reli-
ably associated with an overall difference in familial
risk (14), although some of the specic genetic fac-
tors may differ between men and women (15). For
this reason, some studies stratify their genetic anal-
yses by gender to be sensitive to these effects.
Although too complex to reviewin detail here, an
important consideration for genetic studies of
MDD is psychiatric comorbidity. More than half
of all individuals with MDD develop an anxiety
disorder during their lifetime (16, 17). In addition,
many of those who develop MDD or an anxiety
disorder have elevated premorbid personality traits
such as neuroticism. This observation may be ex-
plained, in part, by the suggestion by some genetic
epidemiological studies that there may be liability
genes that increase risk for internalizing psycho-
pathology in general rather than for specic psychi-
atric disorders. [For reviews of these studies, see
Middeldorp et al. (18) or Hettema (19).] This hy-
pothesis suggests a gene-nding strategy for MDD,
adopted by some groups, that blurs diagnostic
boundaries in choosing subjects for study, such as
including individuals with either MDD or a puta-
tively genetically related condition such as gen-
eralized anxiety disorder or simply studying the
genetics of neuroticism as a continuous trait in the
population.
MOLECULAR GENETIC STUDIES OF
MDD
Once a genetic basis for a condition has been
demonstrated by genetic epidemiological studies,
molecular genetic studies are undertaken to at-
tempt to identify the particular genes underlying
that basis. As explained in greater detail by other
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articles in this issue, the two main types of molec-
ular genetic approaches are linkage and association
studies, as applied to MDD below. Before these are
reviewed in detail, they need to be placed in their
historical context. In classic Mendelian genetic dis-
orders that display specic patterns of familial
transmission such as autosomal dominant or reces-
sive, a relatively rare genetic disease strongly aggre-
gates in certain families due to relatively large det-
rimental effects of a chromosomal abnormality or
changes in a specic gene that changes its func-
tional integrity. However, MDD, with complex
patterns of genetic transmission similar to those of
other common medical conditions such as hyper-
tension or type 2 diabetes, is probably due to the
accumulated effects of many genes of small, more
subtle effects that interact with each other and en-
vironmental factors longitudinally across ones
lifespan to cause an individual to develop the
condition. Many of the early studies, not appreci-
ating this distinction, did not recruit large enough
numbers of subjects, making them insufciently
powered to detect genes of small effect. This limi-
tation applies to both linkage and genetic associa-
tion studies of psychiatric disorders such as MDD,
providing one reason among several to explain why
it has been difcult to unambiguously identify the
liability genes for these conditions.
LINKAGE STUDIES
Linkage studies, necessarily performed in related
individuals such as family pedigrees or sibling pairs,
allowone to roughly locate genetic variation under-
lying a biological trait or condition to particular
regions on a chromosome while reducing the like-
lihood that other regions contain susceptibility loci.
In classic Mendelian disorders in which a relatively
rare genetic disease strongly aggregated in certain
families due to a specic gene, this historically
proved to be a powerful technique for localizing
disease genes. Using this strategy, several groups
performed linkage analyses for MDD, by itself or in
combination with related phenotypes, the main
ndings of which are displayed in Table 1. Few
studies found convincing evidence for linkage (ge-
nome-wide level signicance), and there was little
replication across studies for regions with at least
suggestive linkage. For MDD, only the short armof
chromosome 1 (1p) contained linkage signals in
more than two studies; with this information alone,
it is difcult to determine the potential importance
of other regions reported.
Consistent with genetic epidemiological studies
that support some anxiety disorders and personality
traits such as neuroticism as genetically related to
MDD, a number of linkage scans for these other
Table 1. Genetic Linkage Studies of MDD
Study
Depressive
Phenotype
No. of
Families
Linkage Regions with
Suggestive (*) or
Signicant (**) Linkage Notes
Nurnberger et al., 2001
(20): COGA
Depression/depression
or alcoholism
280/700 7q*/1p** Families ascertained via alcoholic
probands
Zubenko et al., 2003
(21)
RE-MDD 81 1p**, 1q*, 2q*, 5q*, 10q*,
11p**, 11q*, 18q*, 19p*
Further analyses covaried by gender or
linkage to CREB1 gene
Abkevich et al., 2003
(22)
MDD 110 12q** Linkage limited to males
Camp et al., 2005 (23) RE-MDD and/or
anxiety disorders
87 3centr**, 7p*, 18q** Overlapping sample with Abkevich et
al.
McGufn et al., 2005
(24): DeNt
R-MDD 497 1p* Linkage limited to females
Holmans et al., 2007
(25): GenRED
RE-MDD 656 8p*, 15q*, 17p* 8p and 17p linkage seen in sibling
pairs containing males
Middeldorp et al., 2009
(26)
MDD 133 2p*, 8p*, 17p* Population-based twin sample
Kuo et al., 2010 (27):
IASPSAD
MDD/MDDsx 22q*/4q* Families ascertained via alcoholic
probands
COGA, Collaborative Study of the Genetics of Alcoholism; DeNt, Depression Network Study; GenRED, Genetics of Recurrent Early-Onset Depression; IASPSAD, Irish
Affected Sibpair Study of Alcohol Dependence; Depression MDD or depressive syndrome (diagnostic criteria similar to those of MDD except without exclusion
due to substance abuse/other organic causes); R-MDD, recurrent MDD; RE-MDD, recurrent, early-onset MDD; MDDsx, MDD symptoms.
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phenotypes have identied genomic regions that
overlap those from scans involving MDD, as re-
viewed in Fullerton (28) and Levinson (12). A
meta-analysis of eight independent linkage scans
for neuroticism(29) implicated regions on 11q and
12q that overlap with linkage to MDD from
Zubenko et al. (21) and Abkevich et al. (22), re-
spectively. As is generally the case with linkage
studies, the exact location can be quite variable, and
there are typically tens to hundreds of potential
candidate genes in the linked regions.
ASSOCIATION STUDIES
Genetic association studies, which may take the
form of case-control comparisons in unrelated in-
dividuals or family-based transmission tests, allow
one to test specic genes or markers within genes
for their contribution to normal traits or illness.
Most association studies have thus far involved test-
ing one or a few candidate genes implicated indi-
rectly from other data, such as pharmacological
agents (e.g., the gene for the serotonin transporter,
which underlies the mechanism of action of selec-
tive serotonin reuptake inhibitor antidepressants),
stress-related biology (e.g., hypothalamic-pituitary-
adrenal axis genes), or animal models of depression
(e.g., serotonin 1A receptor gene knockouts). The
most popularly studied polymorphism in this re-
spect is the 44-base pair insertion/deletion poly-
morphism (5-HTTLPR) occurring in the pro-
moter region of the serotonin transporter gene
(SLC6A4). Both positive and negative reports
abound for relating this genetic variant to a myriad
of depressive-related phenotypes, making it dif-
cult to draw solid conclusions about its etiological
role. The most recent meta-analyses in MDD
found a modest main effect for the short (S) allele of
this polymorphism (30, 31). Meta-analyses of re-
lated phenotypes suggest that there are small but
statistically signicant effects in association with
neuroticism (3234), suicide (3537), and obses-
sive-compulsive disorder (38) but not panic disor-
der (39). In addition, there is mixed evidence for
and subsequent debate over gene-environment in-
teraction effects between 5-HTTLPR and stressful
life events (4042). Such an interaction implies
that variation in this gene may increase liability to
MDD primarily in individuals who experience sig-
nicant lifetime stressors such as maltreatment or
loss [genetic control of sensitivity to the environ-
ment (43)].
Similar to linkage studies, most genetic associa-
tion studies of MDD have been insufciently pow-
ered because of relatively small sample sizes, result-
ing in a poor record of replicable ndings similar to
other complex traits (44). Meta-analyses attempt
to overcome this limitation by pooling data across
studies, effectively increasing the total sample
analyzed. However, they are often limited by the
inability to include data from all available investi-
gations owing to issues such as heterogeneity be-
tween studies or other criteria designed to maxi-
mize the quality of the results. Besides the serotonin
transporter, separate meta-analyses have examined
association of MDD with the gene encoding the
dopamine D4 receptor (DRD4) (45), methyl-
enetetrahydrofolate reductase (MTHFR) (46), the
serotonin 2A receptor (HTR2A) (47), tyrosine hy-
droxylase (TH) (48), and angiotensin-converting
enzyme (ACE) (49), with only the rst two showing
signicant association across included studies. A re-
cent study reviewed the extant literature for all can-
didate gene association studies of MDD published
before June 2007 (30). This study identied 183
articles that analyzed 393 polymorphisms in 102
candidate genes specically for association with
MDD using acceptable genetic methodology. The
authors performed new meta-analyses for 20 poly-
morphisms in 18 genes that had available data from
three or more studies not included in prior meta-
analyses. Based on their new analyses together with
the prior ones, there is statistical evidence support-
ing some role for at least ve genes in liability
Table 2. Candidate Gene Polymorphisms Implicated in Meta-Analyses of
Genetic Association Studies of MDD
Chromosomal
Region Gene Gene Description Polymorphism
Pooled OR
(95% CI)
1p36.22 MTHFR 5,10-Methylenetetrahydrofolate reductase C677T 1.20 (1.071.34)
5p15.33 SLC6A3 Dopamine transporter (DAT) 40-bp VNTR (3-UTR) 2.06 (1.253.40)
11p15.5 DRD4 Dopamine receptor type 4 48-bp VNTR 1.73 (1.292.32)
12p13.31 GNB3 G-Protein subunit 3 C825T 1.38 (1.131.69)
17q11.2 SLC6A4 Serotonin transporter (SERT) 44-bp Ins/Del (promoter) 1.11 (1.041.19)
OR, odds ratio; CI, condence interval; bp, base pairs; VNTR, variable number tandem repeat; UTR, untranslated region; Ins/Del, insertion/deletion.
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to MDD (listed in Table 2): MTHFR, SLC6A3,
DRD4, GNB3, and SLC6A4. [Note: Since this
analysis, a recent, large study failed to nd associa-
tion with MTHFR (50).] There are probably many
more genes involved in MDD, but either (1) insuf-
cient evidence exists for those already studied be-
cause of too fewor inadequately powered studies or
(2) they have yet not been identied as probable
candidates for study because of our limited under-
standing of the pathophysiology of MDD.
To overcome the latter limitation, complex ge-
netic conditions are now being studied with ge-
nome-wide association studies (GWASs) that use
breakthroughs in high-throughput genotyping
technology to interrogate upward of hundreds of
thousands of polymorphisms across the genome si-
multaneously in one experiment rather than gene
by gene as is done in candidate gene studies. Three
GWASs of MDD have been published to date and
one is in press. The rst, by Muglia et al. (51),
reports the ndings of GWASs in two large, inde-
pendent Caucasian samples: (1) 1,022 patients
with recurrent MDD and 1,000 matched control
subjects recruited from clinical settings in Munich,
Germany, and (2) 492 subjects with recurrent
MDD and 1,052 healthy control subjects recruited
from a community survey in Lausanne, Switzer-
land. The researchers analyzed about 522,000 sin-
gle nucleotide polymorphism(SNP) markers in the
rst sample and about 370,000 in the second. Al-
though the analyses, separately or combined via
meta-analysis, did not provide any ndings meet-
ing formal genome-wide statistical signicance, the
authors provided a table of 27 SNPs on 14 chro-
mosomes that provided nominal but consistent ev-
idence for association to MDD across the two sam-
ples. Of note, all of these are novel ndings; i.e.,
they are in or near genes that have never been ex-
amined before in relation to MDD. The authors
also examined association for candidate genes that
have been tested in prior mood disorder studies;
GRM7, the gene for the metabotrophic glutamate
receptor 7 implicated in a recent GWAS of bipolar
disorder, emerged as the most signicant of these.
Sullivan et al. (52) conducted another large
GWAS using the Genetic Association Information
Network-MDD (GAIN-MDD) sample: 1,738
Dutch subjects with MDD recruited from clinical
and community settings and 1,802 control subjects
selected primarily fromthe Netherlands Twin Reg-
istry as having low genetic liability for depressive or
anxiety disorders. Similar to the rst study, this one
also did not identify any associations with genome-
wide signicance after testing of approximately
435,000 SNPs, and their best signals were from
novel candidates, although with no substantial
overlap with the top candidates as reported in the
rst study. They followed up the most convincing
candidate gene, PCLO on chromosome 7 coding
for the presynaptic protein Piccolo, by testing its
association to MDD in ve independent samples
totaling 6,079 individuals with MDD and 5,893
control subjects. In only one of the replication sam-
ples did several of the PCLO SNPs show modest
association, although, overall, strict guidelines for
replication were not met. However, in a reanalysis
of those data Bochdanovits et al. (53) claimed that
there is support for a role in liability to MDD for a
nonsynonymous coding SNP (rs2522833) in
PCLO. Other replication attempts are currently in
progress. An independent study performed in a
population-based cohort of elderly Dutch individ-
uals recently reported association of rs2522833
with depressive disorders (54).
The third GWAS for MDD (55) was performed
in 1,221 Caucasian patients selected from those
who participated in the Sequenced Treatment Al-
ternatives to Relieve Depression (STAR*D) (56), a
multisite clinical trial; the 1,636 control subjects
were drawn from subjects who screened negative
for MDD, bipolar disorder, or schizophrenia from
the Molecular Genetics of Schizophrenia study in
GAIN (57). That analysis, like the others, did not
identify any markers with genome-wide signi-
cance. Their most strongly associated signals came
from a region containing no known genes on
19q12. In that article, the authors combined their
data with those fromtwo other MDDGWASs: the
Sullivan et al. study in the GAIN-MDD sample
described above and an analysis performed in the
same 1,636 control subjects from the Molecular
Genetics of Schizophrenia sample together with
1,020 subjects from the Genetics of Early-Onset
Major Depression (GenRED) sample (listed in Ta-
ble 1 under linkage analyses) and its follow-up,
GenRED II (58). They performed a meta-analysis
of these three studies using more than 2.4 million
imputed (estimated) SNPs, the most promising of
which implicated three genes: (1) ATP6V1B2 on
8p21.3, a gene also modestly implicated in a bipo-
lar disorder GWAS that encodes for a vacuolar pro-
ton ATPase, (2) SP4 on 7p15.3, encoding a brain-
specic zinc-nger transcription factor, and (3)
GRM7 on 3p26.1, the same metabotrophic gluta-
mate receptor gene mentioned in the rst MDD
GWAS above.
CONCLUSIONS
MDD is a common condition that aggregates in
families to a modest degree, most likely due to a
large number of genes of small effect. It probably
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shares some of its genetic risk factors with other
internalizing phenotypes such as neuroticism and
the anxiety disorders. Linkage studies have not
strongly and consistently implicated any specic
regions in the genome for harboring susceptibility
loci for MDD, a problem that has plagued linkage
analyses of other complex disorders. Although hun-
dreds of candidate gene association studies have
been published, meta-analyses report only modest
evidence supporting ve genes thus far: MTHFR
(related to folate metabolism), SLC6A3 (dopamine
transporter), DRD4 (dopamine receptor type 4),
GNB3 (G-protein subunit 3), and SLC6A4 (se-
rotonin transporter). Thus far, available GWAS
data suggest a number of novel susceptibility can-
didates, including replicated support for the gluta-
mate receptor gene GRM7 gene and, possibly,
PCLO; the prior ve candidate genes were not
among the top-ranked loci. More powerful
GWASs, meta-analyses, and replication studies are
forthcoming, so this is a rapidly moving target. Ex-
cept for the serotonin transporter gene, models of
gene-environment interaction in MDD, probably
an important factor in understanding how genetic
factors and life events produce illness in some indi-
viduals but not others, have been explored in few
studies. Thus, there is still much work to be done
before a clear understanding of depression suscep-
tibility genes and their role in the development of
MDD will be attained.
R E F E R E N C E S
1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush
AJ, Walters EE, Wang PS: The epidemiology of major depressive disorder:
results from the National Comorbidity Survey Replication (NCS-R). JAMA
2003; 289:30953105
2. Moftt TE, Caspi A, Taylor A, Kokaua J, Milne BJ, Polanczyk G, Poulton,
R: How common are common mental disorders? Evidence that lifetime
prevalence rates are doubled by prospective versus retrospective ascer-
tainment. Psychol Med 2009; doi: 10.1017/S0033291709991036
3. Patten SB: Accumulation of major depressive episodes over time in a
prospective study indicates that retrospectively assessed lifetime prev-
alence estimates are too low. BMC Psychiatry 2009; 9:19
4. Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT: Prevalence
and predictors of recurrence of major depressive disorder in the adult
population. Acta Psychiatr Scand (in press)
5. Murray CJ, Lopez AD: Alternative projections of mortality and disability by
cause 19902020: Global Burden of Disease Study. Lancet 1997; 349:
14981504
6. Kendler KS, Gardner CO Jr: Boundaries of major depression: an evalua-
tion of DSM-IV criteria. Am J Psychiatry 1998; 155:172177
7. Sullivan PF, Neale MC, Kendler KS: Genetic epidemiology of major
depression: review and meta-analysis. Am J Psychiatry 2000; 157:1552
1562
8. Neale MC, Cardon LR: Methodology for Genetic Studies of Twins and
Families. Dordrecht, The Netherlands, Kluwer Academic BV, 1992
9. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: The lifetime
history of major depression in women. Reliability of diagnosis and
heritability. Arch Gen Psychiatry 1993; 50:863870
10. Paykel ES: Life events, social support and depression. Acta Psychiatr
Scand Suppl 1994; 377:5058
11. Kessler RC: The effects of stressful life events on depression. Annu Rev
Psychol 1997; 48:191214
12. Levinson DF: The genetics of depression: a review. Biol Psychiatry 2006;
60:8492
13. Bebbington PE: Sex and depression. Psychol Med 1998; 28:18
14. Merikangas KR, Weissman MM, Pauls DL: Genetic factors in the sex ratio
of major depression. Psychol Med 1985; 15:6369
15. 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; 31:605616
16. Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG:
Comorbidity of DSM-III-R major depressive disorder in the general
population: results from the US National Comorbidity Survey [see com-
ments]. Br J Psychiatry Suppl 1996; 168:1730
17. Regier DA, Rae DS, Narrow WE, Kaelber CT, Schatzberg AF: Prevalence
of anxiety disorders and their comorbidity with mood and addictive
disorders. Br J Psychiatry Suppl 1998; 173:2428
18. Middeldorp CM, Cath DC, van Dyck R, Boomsma D: The co-morbidity of
anxiety and depression in the perspective of genetic epidemiology. A
review of twin and family studies. Psychol Med 2005; 35:611624
19. Hettema JM: What is the genetic relationship between anxiety and
depression? Am J Med Genet C Semin Med Genet 2008; 148C:140146
20. Nurnberger JI Jr, Foroud T, Flury L, Su J, Meyer ET, Hu K, Crowe R,
Edenberg H, Goate A, Bierut L, Reich T, Schuckit M, Reich W: Evidence
for a locus on chromosome 1 that inuences vulnerability to alcoholism
and affective disorder. Am J Psychiatry 2001; 158:718724
21. Zubenko GS, Maher B, Hughes HB III, Zubenko WN, Stifer JS, Kaplan BB,
Marazita ML: Genome-wide linkage survey for genetic loci that inuence
the development of depressive disorders in families with recurrent,
early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet
2003; 123:118
22. Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC, Plenk
AM, Lowry MR, Richards RL, Carter C, Frech GC, Stone S, Rowe K, Chau
CA, Cortado K, Hunt A, Luce K, ONeil G, Poarch J, Potter J, Poulsen GH,
Saxton H, Bernat-Sestak M, Thompson V, Gutin A, Skolnick MH, Shattuck
D, Cannon-Albright L: Predisposition locus for major depression at chro-
mosome 12q2212q23.2. Am J Hum Genet 2003; 73:12711281
23. Camp NJ, Lowry MR, Richards RL, Plenk AM, Carter C, Hensel CH,
Abkevich V, Skolnick MH, Shattuck D, Rowe KG, Hughes DC, Cannon-
Albright LA: Genome-wide linkage analyses of extended Utah pedigrees
identies loci that inuence recurrent, early-onset major depression and
anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2005;
135:8593
24. McGufn P, Knight J, Breen G, Brewster S, Boyd PR, Craddock N, Gill M,
Korszun A, Maier W, Middleton L, Mors O, Owen MJ, Perry J, Preisig M,
Reich T, Rice J, Rietschel M, Jones L, Sham P, Farmer AE: Whole genome
linkage scan of recurrent depressive disorder from the depression net-
work study. Hum Mol Genet 2005; 14:33373345
25. Holmans P, Weissman MM, Zubenko GS, Scheftner WA, Crowe RR,
DePaulo JR, Knowles JA, Zubenko WN, Murphy-Eberenz K, Marta DH,
Boutelle S, McInnis MG, Adams P, Gladis M, Steele J, Miller EB, Potash
JB, MacKinnon DF, Levinson DF: Genetics of recurrent early-onset major
depression (GenRED): Final genome scan report. Am J Psychiatry 2007;
164:248258
26. Middeldorp CM, Sullivan PF, Wray NR, Hottenga JJ, de Geus EJ, van den
Berg M, Montgomery GW, Coventry WL, Statham DJ, Andrews G, Slag-
boom PE, Boomsma DI, Martin NG: Suggestive linkage on chromosome 2,
8, and 17 for lifetime major depression. Am J Med Genet B Neuropsy-
chiatr Genet 2009; 150B:352358
27. Kuo PH, Neale MC, Walsh D, Patterson DG, Riley B, Prescott CA, Kendler
KS, Genome-wide linkage scans for major depression in individuals with
alcohol dependence. J Psychiatr Res 2010; doi: 10.1016/j.psy-
chires.2009.12.005
28. Fullerton J: New approaches to the genetic analysis of neuroticism and
anxiety. Behav Genet 2006; 36:147161
29. Hettema JM: Meta-analyses of genome-wide linkage scans of anxiety-
related phenotypes, in XVIth World Congress on Psychiatric Genetics
Proceedings. Osaka, Japan, 2008
30. Lopez-Leon S, Janssens AC, Gonzalez-Zuloeta Ladd AM, Del Favero J,
Claes SJ, Oostra BA, van Duijn CM: Meta-analyses of genetic studies on
major depressive disorder. Mol Psychiatry 2008; 13:772785
31. Kiyohara C, Yoshimasu K: Association between major depressive disorder
and a functional polymorphism of the 5-hydroxytryptamine (serotonin)
transporter gene: a meta-analysis. Psychiatr Genet (in press)
32. Sen S, Burmeister M, Ghosh D: Meta-analysis of the association between
a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-
related personality traits. Am J Med Genet B Neuropsychiatr Genet 2004;
127:8589
33. Schinka JA, Busch RM, Robichaux-Keene N: A meta-analysis of the
association between the serotonin transporter gene polymorphism (5-
HTTLPR) and trait anxiety. Mol Psychiatry 2004; 9:197202
34. Munafo MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J, Jarvelin
MR, Taanila A, Flint J: 5-HTTLPR genotype and anxiety-related person-
HETTEMA
focus.psychiatryonline.org FOCUS Summer 2010, Vol. VIII, No. 3
321
C
L
I
N
I
C
A
L
S
Y
N
T
H
E
S
I
S
ality traits: a meta-analysis and new data. Am J Med Genet B Neuro-
psychiatr Genet 2009; 150B:271281
35. Anguelova M, Benkelfat C, Turecki G: A systematic review of association
studies investigating genes coding for serotonin receptors and the sero-
tonin transporter: II. Suicidal behavior. Mol Psychiatry 2003; 8:646653
36. Lin PY, Tsai G: Association between serotonin transporter gene promoter
polymorphism and suicide: results of a meta-analysis. Biol Psychiatry
2004; 55:10231030
37. Li D, He L: Meta-analysis supports association between serotonin trans-
porter (5-HTT) and suicidal behavior. Mol Psychiatry 2007; 12:4754
38. Lin PY: Meta-analysis of the association of serotonin transporter gene
polymorphism with obsessive-compulsive disorder. Prog Neuropsychop-
harmacol Biol Psychiatry 2007; 31:683689
39. Blaya C, Salum GA, Lima MS, Leistner-Segal S, Manfro GG: Lack of
association between the serotonin transporter promoter polymorphism
(5-HTTLPR) and panic disorder: a systematic review and meta-analysis.
Behav Brain Funct 2007; 3:41
40. Caspi A, Sugden K, Moftt TE, Taylor A, Craig IW, Harrington H, McClay
J, Mill J, Martin J, Braithwaite A, Poulton R: Inuence of life stress on
depression: moderation by a polymorphism in the 5-HTT gene. Science
2003; 301:386389
41. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs
M, Ott J, Merikangas KR: Interaction between the serotonin transporter
gene (5-HTTLPR), stressful life events, and risk of depression: a meta-
analysis. JAMA 2009; 301:24622471
42. Rutter M: Gene-environment interplay. Depress Anxiety 2010; 27:14
43. Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC,
Eaves LJ: Stressful life events, genetic liability, and onset of an episode
of major depression in women. Am J Psychiatry 1995; 152:833842
44. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K: A comprehensive
review of genetic association studies. Genet Med 2002; 4:4561
45. Lopez LS, Croes EA, Sayed-Tabatabaei FA, Claes S, Van Broeckhoven C,
van Duijn CM: The dopamine D4 receptor gene 48-base-pair-repeat
polymorphism and mood disorders: a meta-analysis. Biol Psychiatry
2005; 57:9991003
46. Lewis SJ, Lawlor DA, Davey SG, Araya R, Timpson N, Day IN, Ebrahim S:
The thermolabile variant of MTHFR is associated with depression in the
British Womens Heart and Health Study and a meta-analysis. Mol
Psychiatry 2006; 11:352360
47. Anguelova M, Benkelfat C, Turecki G: A systematic review of associa-
tion studies investigating genes coding for serotonin receptors and the
serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8:574
591
48. Furlong RA, Rubinsztein JS, Ho L, Walsh C, Coleman TA, Muir WJ, Paykel
ES, Blackwood DH, Rubinsztein DC: Analysis and metaanalysis of two
polymorphisms within the tyrosine hydroxylase gene in bipolar and
unipolar affective disorders. Am J Med Genet 1999; 88:8894
49. Lopez-Leon S, Janssens AC, Hofman A, Claes S, Breteler MM, Tiemeier
H, van Duijn CM: No association between the angiotensin-converting
enzyme gene and major depression: a case-control study and meta-
analysis. Psychiatr Genet 2006; 16:225226
50. Gaysina D, Cohen S, Craddock N, Farmer A, Hoda F, Korszun A, Owen MJ,
Craig IW, McGufn P: No association with the 5,10-methylenetetrahy-
drofolate reductase gene and major depressive disorder: results of the
depression case control (DeCC) study and a meta-analysis. Am J Med
Genet B Neuropsychiatr Genet 2008; 147B:699706
51. Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ,
Antoniades A, Domenici E, Perry J, Rothen S, Vandeleur CL, Mooser V,
Waeber G, Vollenweider P, Preisig M, Lucae S, Muller-Myhsok B, Hols-
boer F, Middleton LT, Roses AD: Genome-wide association study of
recurrent major depressive disorder in two European case-control co-
horts. Mol Psychiatry 2008; doi: 10.1038/mp.2008.131
52. Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T,
Arolt V, Baune BT, Blackwood D, Cichon S, Coventry WL, Domschke K,
Farmer A, Fava M, Gordon SD, He Q, Heath AC, Heutink P, Holsboer F,
Hoogendijk WJ, Hottenga JJ, Hu Y, Kohli M, Lin D, Lucae S, Macintyre DJ,
Maier W, McGhee KA, McGufn P, Montgomery GW, Muir WJ, Nolen WA,
Nothen MM, Perlis RH, Pirlo K, Posthuma D, Rietschel M, Rizzu P,
Schosser A, Smit AB, Smoller JW, Tzeng JY, van Dyck R, Verhage M,
Zitman FG, Martin NG, Wray NR, Boomsma DI, Penninx BW: Genome-
wide association for major depressive disorder: a possible role for the
presynaptic protein piccolo. Mol Psychiatry 2009; 14:359375
53. Bochdanovits Z, Verhage M, Smit AB, de Geus EJ, Posthuma D, Boomsma
DI, Penninx BW, Hoogendijk WJ, Heutink P: Joint reanalysis of 29
correlated SNPs supports the role of PCLO/Piccolo as a causal risk factor
for major depressive disorder. Mol Psychiatry 2009; 14:650652
54. Hek K, Mulder CL, Luijendijk HJ, van Duijn CM, Hofman A, Uitterlinden AG,
Tiemeier H: The PCLO gene and depressive disorders: replication in a
population-based study. Hum Mol Genet 2010; 19:731734
55. Shyn SI, Shi J, Kraft JB, Potash JB, Knowles JA, Weissman MM, Garriock
HA, Yokoyama JS, McGrath PJ, Peters EJ, Scheftner WA, Coryell W,
Lawson WB, Jancic D, Gejman PV, Sanders AR, Holmans P, Slager SL,
Levinson DF, Hamilton SP: Novel loci for major depression identied by
genome-wide association study of Sequenced Treatment Alternatives to
Relieve Depression and meta-analysis of three studies. Mol Psychiatry
2009; doi: 10.1038/mp.2009.125
56. Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA,
Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosen-
baum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K,
Lebowitz BD, Ritz L, Niederehe G: Sequenced treatment alternatives to
relieve depression (STAR*D): rationale and design. Control Clin Trials
2004; 25:119142
57. Manolio TA, Rodriguez LL, Brooks L, Abecasis G, Ballinger D, Daly M,
Donnelly P, Faraone SV, Frazer K, Gabriel S, Gejman P, Guttmacher A,
Harris EL, Insel T, Kelsoe JR, Lander E, McCowin N, Mailman MD, Nabel
E, Ostell J, Pugh E, Sherry S, Sullivan PF, Thompson JF, Warram J,
Wholley D, Milos PM, Collins FS: New models of collaboration in genome-
wide association studies: the Genetic Association Information Network.
Nat Genet 2007; 39:10451051
58. Shi J, Potash JB, Knowles JA, Weissman MM, Coryell W, Scheftner WA,
Lawson WB, Depaulo JR Jr, Gejman PV, Sanders AR, Johnson JK, Adams
P, Chaudhury S, Jancic D, Evgrafov O, Zvinyatskovskiy A, Ertman N,
Gladis M, Neimanas K, Goodell M, Hale N, Ney N, Verma R, Mirel D,
Holmans P, Levinson DF: Genome-wide association study of recurrent
early-onset major depressive disorder. Mol Psychiatry 2010; doi:
10.1038/mp.2009.124
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Summer 2010, Vol. VIII, No. 3 F O C U S THE J OURNAL OF LI FELONG LEARNI NG I N PS YCHI ATRY
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