Molecular genetics of affective disorders

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Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 865–877

Review article

Molecular genetics of affective disorders

Pierre Oswald*, Daniel Souery, Julien Mendlewicz

Department of Psychiatry, Erasme Hospital, Free University of Brussels, 808 route de Lennik, B-1070, Brussels, Belgium

Accepted 10 May 2004

Available online 23 July 2004

Abstract

Evidence for familial aggregation in Affective Disorders (AD) has been provided in classical studies. Linkage and association genetic studies

have been proposed to detect genetic factors implicated in AD. However, findings from molecular genetic studies remain inconclusive.

Nevertheless, current research is focusing on the phenotypes, both sub- and endophenotypes. In addition, recent advances in technology, such as

microarrays, provide new tools in psychiatric genetics. These different approaches offer a new optimism era in the search of genetic factors in AD.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Affective Disorders; Anticipation; Association; Ethics; Linkage; Molecular genetics

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865

2. The clinical evidence in favour of a genetic component for AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

3. Finding the genes: linkage and association methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

4. Linkage studies with DNA markers in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

5. Association studies and candidate genes in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867

5.1 Serotonergic and monoaminergic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867

5.2 GABAergic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868

5.3 Other candidate genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869

6. Anticipation and expanded trinucleotide repeat sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869

7 How to improve the genetic studies in affective disorders?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870

7.1 Search for phenotypes in affective disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870

7.2 Improving genetic techniques and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871

8 Ethical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871

9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872

1. Introduction

Despite significant advances in treatment strategies,

Affective Disorders (AD) remain a problem not only in

terms of quality of life but also of health economics.

Research investigations have focused during the last

0278-5846/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.pnpbp.2004.05.028

Abbreviations: AD, Affective Disorder; BPAD, bipolar affective

disorder; LD, linkage disequilibrium; RFLP, restriction fragment length

polymorphism; UPAD, unipolar affective disorder.

* Corresponding author.

E-mail address: [email protected] (P. Oswald).

decades on the aetiology of the disease. Historical obser-

vations have consistently provided evidence for a genetic

component in the vulnerability to AD (Mendlewicz, 1994;

McGuffin et al., 1994). These evidences have demonstrat-

ed that a single-gene dysfunction is not enough to explain

the mode of inheritance, which is more complex and may

include non-Mendelian patterns. We will review the

current findings in the field of molecular genetic studies

of Unipolar (UPAD) and Bipolar Affective Disorders

(BPAD). In addition, we will discuss how to improve

the current genetic studies in psychiatry. Finally, ethical

aspects will be considered.

P. Oswald et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 865–877866

2. The clinical evidence in favour of a genetic component

for AD

Evidence from classical studies demonstrates the presence

of a familial aggregation for AD (Sklar et al., 2002). Familial

aggregation means that a trait clusters among multiple

members of a family (Kamnasaran, 2003). Findings from

clinical chart data show that families with relatives with AD

have increased occurrence of the trait segregating among

them. However, familial aggregation studies are not sufficient

to indicate a genetic basis in AD, since the trait can also

possibly be related to environmental factors. Heritability

studies provide an interesting approach to estimate the

variance of the genetic component among affected families

(Kamnasaran, 2003). A genetic aetiology is proposed when

the variance is >30% for a trait in affected families. In recent

studies, the calculated variance is as high as 80% in BPAD

and around 50% in UPAD (Bennett et al., 2002; Maier et al.,

2003). Finally, twin and adoption studies have been imple-

mented to explore the heritability of AD by controlling

environmental factors. Evidence from twin studies has shown

that the concordance rate between monozygotic twin pairs

ranges from 50% for UPAD to 75% for BPAD, indicating that

these phenotypes are mainly, but not strictly, from genetic

origin. Finally, in adoption studies, AD have been described

to be higher in biological relatives of the adopted subject,

suffering fromAD than in adopted relatives (Mendlewicz and

Rainer, 1977; Bennett et al., 2002).

3. Finding the genes: linkage and association methods

The initial molecular genetic approach of AD involved

the parametric linkage studies of large families (Merikangas

et al., 1989; Risch and Merikangas, 1993; Souery et al.,

2001a). Linkage examines the cosegregation of a genetic

marker and disease in affected individuals within families,

that is, the non-random sharing of marker alleles between

affected members of each family. Two genetic loci are

linked if they are located closely together on a chromosome.

In linkage analysis, the frequency of meiotic recombinations

as an expression of the distance between marker locus and

the gene under investigation is used for gene mapping. The

classical method that has been successfully applied in

linkage studies is the LOD score (Schulze and McMahon,

2003). The LOD score is the log10 of the ratio LHa/LH10: the

likelihood (LHa) of the observed constellation of the disease

and marker data assuming linkage, compared to the likeli-

hood (LH10) of observing the same data assuming no

linkage. The traditional threshold of a LOD score >3.0

has been proposed to achieve a true significant linkage.

This threshold must not be considered as the golden

standard, since different methods have been studied, leading

to different values (Schulze and McMahon, 2003). More

recently, genome-wide linkage studies have been performed

on samples of families with multiply affected members

(Segurado et al., 2003; Maier et al., 2003). Marker systems

(restriction fragment length polymorphisms [RFLP] or

microsatellite marker systems) screen the whole genome

in search of candidate regions with predisposing genes,

which can be detected by subsequent sequencing and fine-

mapping or by focus on candidate genes located in these

intervals.

Considering the difficulties inherent in detecting genes

of small to modest effect using the linkage approach in

complex traits, the candidate gene association method

offers an alternative strategy of studying genetic factors

involved in complex diseases in which the mode of

inheritance is unknown. Association method compares

the allele frequencies between a control sample and sample

that suffers from the disease. Association between diseases

and markers may be found if the gene itself, or a locus in

linkage disequilibrium (LD) with the marker, is involved in

the pathophysiology of the disease (Hodge, 1994). Thus,

an association may imply a direct effect of the gene tested,

or the effect of another gene close to the marker examined.

This has important implication for replication in subse-

quent works. For example, as shown by Schulze and

McMahon (2003), if the associated marker is the causal

variant, the same allele should show association in other

populations. If the associated marker is in LD with the

causal variant, then different alleles may be implicated and

show association in other populations. However, the can-

didate gene approach remains a useful method to investi-

gate association between markers and disease. Two slightly

association different strategies are available: case-control

and family-based. Family-based approach seemed to be

more powerful, in reducing the risk of false-positive,

inherent to population stratification in case-control studies.

However, stratification problem seems to be less marked in

more homogenous populations such as those in Western

Europe (Pritchard and Rosenberg, 1999). Moreover, case-

control design permits to achieve a representative sample

of patients because family-based samples may show some

bias (Brunn and Ewald, 1999). As suggested by Craddock

et al. (2001), case-control and family-based association

samples have complementary roles in searching for genes

involved in AD.

4. Linkage studies with DNA markers in AD

In view of the plethora of linkage studies published, we

present here an update of replicated and/or representative

findings (previously reviewed in the works of Souery et al.,

2001a and Oswald et al., 2003a). Reviewing more than two

decades of linkage investigations in AD, it appears that

significant proportion of positive DNA findings involves

several chromosome regions (Turecki et al., 1996). Mend-

lewicz et al. (1987) first reported possible genetic linkage

between BPAD and coagulation Factor IX located at Xq27 in

11 pedigrees. Since then, several linkage studies with X

P. Oswald et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 865–877 867

markers revealed different results (Berrettini et al., 1990;

Bredbacka et al., 1993; Gejman et al., 1990; Lucotte et al.,

1992). Nevertheless, more recent studies showed that sug-

gestive results of X linkage and in particular the Xq26–28

region should be considered as a strong candidate region for

genetic studies in BPAD (De bruyn et al., 1994; Pekkarinen et

al., 1995; Stine et al., 1997). Another region of interest seems

to be the chromosome 18 where the pericentromeric region

was suggested to carry susceptibility genes (Berrettini et al.,

1994; Gershon et al., 1996; Stine et al., 1995; Kamnasaran,

2003). This result is of interest because genes coding for the a

unit of a GTP binding protein involved in neurotransmission,

a corticotrophin receptor gene, and RED-1 containing triplet

repeats have been mapped to this region. The John Hopkins

group also studied a set of 30 families supporting linkage at

18q21 (McMahon et al., 1997). Other groups also found

evidence for linkage at 18q12, 18q22 and 18q23 (De bruyn et

al., 1996; Ewald et al., 1997; Nothen et al., 1999). Concerning

18q23, findings from Freimer et al. (1996) were the strongest

at an estimated 80–82 Mb from the p-telomere. The chro-

mosome 11 has been thoroughly investigated in AD but

showed contradictory results (Egeland et al., 1987; Gurling

et al., 1995; Lim et al., 1993; Smyth et al., 1996; Byerley et

al., 1992; Holmes et al., 1991; Nanko et al., 1994; Souery and

Mendlewicz, 1995). Chromosomes 4, 6 and 10 were also

investigated with conflicting and/or unreplicated results

(Smeraldi et al., 1978; Stancer et al., 1988; Turner and King,

1981, 1983; Weitkamp et al., 1981; Blackwood et al., 1996;

Cichon et al., 2001). Darier’s disease (keratosis follicularis), a

rare autosomal dominant skin disorder associated with in-

creased prevalence of epilepsy and mental retardation, whose

gene was mapped on chromosome 12 (12q23–24.1), was

found to cosegregate with BPAD in one pedigree. This result

was replicated in several family studies (Aita et al., 1999;

Detera-Wadleigh et al., 1996, 1997; Straub et al., 1994).

Finally, Blackwood et al. (2001) reported recently strong

evidence of linkage in a family with a (1;11)(q42;q14.3)

translocation. Genome-wide linkage analyses provide an

accurate tool to study regions of interest (see above). In

BPAD, early positive and promising results were contradicted

by further analyses. This fact is not surprising, since these

studies were performed on small samples sizes, insufficient to

replicate modest linkage signals (Suarez and Hampe, 1994).

Metaanalyses were thus performed on BPAD to increase the

power to detect modest linkage signals (Lewis et al., 2003;

Segurado et al., 2003; Maier et al., 2003). Bipolar loci with

evidence of linkage were found on the following arms: 9p,

10q, 14q and 18p–q (Maier et al., 2003).

5. Association studies and candidate genes in AD

As mentioned above, association studies are best applied

if candidate genes are selected. Such candidate alleles are

chosen on the basis of the current understanding of the

biology of the disorder. Therefore, genes related to seroto-

nergic and monoaminergic pathways have been firstly

considered as the targets for association studies during the

last years (Fig. 1).

5.1. Serotonergic and monoaminergic pathways

Several polymorphisms in serotonergic and monoaminer-

gic related-genes have been studied (Potash and DePaulo,

2000). The tyrosine hydroxylase (TH) gene, located on

11p15.5, is a candidate gene extensively explored in associ-

ation studies in AD. Although some studies showed promis-

ing results (Perez et al., 1995; Oruc et al., 1997a), two meta-

analyses have failed to confirm the implication of TH gene

both in UPAD and BPAD (Furlong et al., 1999; Turecki et al.,

1997). The tryptophan hydroxylase gene (TPH), located on

11p15.3–p14, includes two identified polymorphisms

(A218C and A779C) (Bellivier et al., 1998; Nielsen et al.,

1997). Souery et al. (2001b), in a recent large multicenter

study, found no association between A218C polymorphism

and UPAD and BPAD. The monoamine oxidase A (MAOA)

gene, located on Xp11.23, has been studied in 16 and 7

association studies for BPAD and UPAD, respectively, with

conflicting results (Lim et al., 1995; Rubinsztein et al., 1996;

Kunugi et al., 1999; Ho et al., 2000; Lin et al., 2000; Preisig et

al., 2000; Syagailo et al., 2001). The catechol-O-methyltrans-

ferase (COMT) gene, located on 22q11.2, is implicated in

dopamine and noradrenaline degradation. A large number of

studies failed to show an implication of COMT gene in AD

(Biomed European Bipolar Collaborative Group, 1997;

Kunugi et al., 1997). Kirov et al. (1999) failed to show an

association between dopamine h-hydroxylase gene (DBH),

located on 9q34, and BPAD. The serotonin, dopamine and

noradrenaline transporter genes (5-HTT, DAT1 and NET),

located on 17q11.1–12, 5p15.3 and 16q12.2, respectively,

were also studied. A study concluded that 5-HTT has no

major role in the aetiology of BPAD (Craddock et al., 2001).

On the other hand, various studies support a relative influence

of 5-HTT in UPAD (Battersby et al., 1996; Collier et al.,

1996; Ogilvie et al., 1996). More recently, Mendlewicz et al.

(2004) showed in a sample of 539 UPAD, 572 BPAD and 821

controls a lack of association between 5-HTT and AD.

Studies on DAT1 and NET are largely negative (Craddock

et al., 2001). Serotonin receptors genes, principally 5-HT2A

(13q14–21), 5-HT2C (Xq24), 5-HT3A (11q23.1) and 5-HT7

(10q21–24) genes, were studied in several association stud-

ies but no definitive positive association was found (Oswald

et al., 2003b; Potash and DePaulo, 2000). D2 receptor gene

(DRD2), located on 11q22.2–22.3, was extensively studied

in BPAD and UPAD. In BPAD, most studies are negative

(Massat et al., 2002b). But a positive association was recently

found in a large sample of 716 subjects (Massat et al., 2002b).

D1, D3, D4 and D5 receptors genes (DRD1, DRD3, DRD4

and DRD5) located respectively on 5q35.1, 3q13.3, 11p15.5

and 4p15.3–16.1 have been shown not to be implicated in

AD in most studies (Asherson et al., 1998; Lim et al., 1994;

Savoye et al., 1998; Souery et al., 1996).

Hydroxylase

Fig. 1. Serotonergic and monoaminergic pathways and candidate genes in affective disorders.


5.2. GABAergic pathway

Available data on gamma amino butyric acid (GABA)

support the hypothesis that a dysfunction in the brain

GABAergic system activity contributes to vulnerability to

AD (Massat et al., 2000). Receptor activity is modulated

according to the subunit’s combination within five distinct

classes. Recent association studies concerned genes coding

for the a1 (GABRA1), a3 (GABRA3), and a5 (GABRA5)

subunits, located respectively on 5q34–q35, Xq28 and

15q11–q13. Results for GABRA1 are conflicting (Walsh

et al., 1992; Serretti et al., 1998; Horiuchi et al., 2004).


Massat et al. (2002a) showed a significant association

between the GABRA3 polymorphism and the occurrence

of BPAD, particularly in females. This result was not

replicated in UPAD (Massat et al., 2001). GABRA5 is

implicated in UPAD and BPAD in two association studies

but needs to be replicated (Papadimitriou et al., 1998; Oruc

et al., 1997a).

5.3. Other candidate genes

In addition to the classical pathways presented above, it is

now possible to investigate the genetics of enzymes and

receptors involved in novel and promising metabolic routes

such as neuroprotection or neurotrophy. Substance P (SP)

pathway has recently focused interest. In fact, SP antagonists

were found to be as effective as SSRIs in UPAD with limited

side effects (Kramer et al., 1998, 2004). The angiotensin

converting enzyme (ACE) gene is responsible of SP degra-

dation and is therefore a good candidate gene for association

studies in AD. An insertion/deletion polymorphism was

identified. Five association studies were conducted but only

one found an association with AD (Arinami et al., 1996;

Baghai et al., 2001; Furlong et al., 2000; Meira-Lima et al.,

2000; Pauls et al., 2000). Other genes of SP metabolism are

under investigation since their polymorphisms have been

identified (i.e. SP receptor (NK1R) gene, SP precursor

(TAC1) or peptidylglycine alpha-amidating monooxygenase

(PAM) gene). Neurotrophic factors have recently focused

interest since one of them, Brain-Derived Neurotrophic

Factor (BDNF) has been shown to be implicated in AD and

in response to mood stabilizers and antidepressants (Nibuya

et al., 1995; Duman, 1998; Fukumoto et al., 2001). Two

family-based association studies recently demonstrated an

association between BDNF and BPAD (Neves-Pereira et al.,

2002; Sklar et al., 2002). Also, these results were not

confirmed in two recent case-control association studies

(Nakata et al., 2003; Oswald et al., in press). More recently,

Tsai et al. (2003) found no association between BDNF and

UPAD. Most recent papers have provided consistent argu-

ments in favour of an influence of G72 gene in BPAD (Hattori

et al., 2003; Chen et al., 2004; Schumacher et al., 2004). This

gene, located in the 13q candidate region for schizophrenia,

suggests that these two psychiatric disorders may share some

of their etiologic background.

6. Anticipation and expanded trinucleotide repeat

sequences

Anticipation implies that a disease occurs at a progres-

sively earlier age of onset and with increased severity in

successive generations. This phenomenon has been ob-

served in several neurological diseases including myotonic

dystrophy, fragile X syndrome and Huntington’s disease

(Paulson and Fischbeck, 1996; Trottier et al., 1995). Antic-

ipation has been found to correlate with a new class of

mutations, expanded trinucleotide repeat sequences. An

expanded repeat sequence is unstable and may increase in

size across generations, leading to an increased disease

severity of the disorder. Such unstable mutations could also

be an alternative explanation in addition to environmental

factors for discordance between monozygotic twins for AD

where the repeat amplification might be different during

mitosis in each of the two twins.

Evidence for anticipation has been observed in AD

(Engstrom et al., 1995; McInnis et al., 1993; Nylander et

al., 1994). Correlation between anticipation observed at the

phenotypic level with the number of dynamic mutations

may be the only way to confirm the implication of this

phenomenon in mood disorders. One study highlighted an

association between the number of CAG trinucleotide

repeats and severity of BPAD illness in Swedish and

Belgian patients (Lindblad et al., 1995). This study, repli-

cated subsequently in a different sample (O’Donovan et al.,

1995; Oruc et al., 1997b), showed for the first time in a

major psychiatric disorder that the length of CAG repeats

was significantly higher in BPAD compared to normal

controls. These molecular genetic findings may indicate a

genetic basis for anticipation in BPAD. However, no corre-

lation has been found between CAG/CTG repeats and

phenotypic measures of severity in several studies (Crad-

dock et al., 1997; Guy et al., 1999; Li et al., 1998; Vincent et

al., 1996; Zander et al., 1998). This hypothesis has recently

been tested in a sample of two-generation pairs with BPAD.

Globally, no significant differences were found in the mean

number of CAG repeats between parent and offspring

generations. A significant increase in CAG repeats between

parents and offspring was observed, however, when the

phenotype increased in severity, i.e. changed from major

depression, single episode or unipolar recurrent depression

to BPAD (Mendlewicz et al., 1997). A significant increase

in CAG repeats length between generations was also found

in female offspring with maternal inheritance, but not in

male offspring. This is the first evidence of genetic antici-

pation in BPAD families and has been followed by the

identification of loci within the genome containing triplet

repeats. CTG 18.1 on chromosome 18q21.1 and ERDA 1 on

chromosome 17q21.3 are two repeat loci recently identified

(Lindblad et al., 1998) which can be investigated in such

study. In this study, several hundreds of candidate loci

containing repeats were screened in a set of BPAD patients

and expanded alleles at ERDA1 and CTG18.1 loci were

found to be associated with BPAD phenotype. The authors

observed that in a Swedish sample, including both unrelated

and familial cases, 89% of expanded RED products corre-

late with expansions at these two loci and that expansion at

the CTG18.1 locus was associated to the phenotype. Using

the same method in a Belgian sample, Verheyen et al. (1999)

demonstrated that 86% of the RED expansions could be

accounted for by ERDA1 and CTG18.1 repeats (Verheyen

et al., 1999). Expanded alleles at ERDA1 were found to be

more frequent in bipolar patients. Eight CAG/CTG triplet


repeats located in the 18q21.33–q23, identified as a candi-

date region in bipolar families, have been investigated in

bipolar disorder by Goossens et al. (2000), but no expansion

has been found in the bipolar family and the case-control

sample.

7. How to improve the genetic studies in affective

disorders?

The plethora of results presented above may be viewed

as contradictory. As illustrated in this review, once a locus or

a polymorphism is claimed, one or more subsequent studies

cannot confirm it. Positive findings from association studies

are not always confirmed and more than one chromosomal

regions are proposed for the same phenotype. Different

reasons for the lack of unambiguously detected locus of

interest are evoked. First, the transmission patterns of AD

are complex. Environmental and genetic factors are in-

volved in the occurrence of such disorders. In addition, it

is anticipated that multiple deleterious genetic variants are

required in combination and that individual genes alone are

not sufficient (epistasis) (Souery et al., 2001a). Another

controversial issue is the phenotype definition. It is not

clearly established that the classical diagnostic categories

investigated, i.e. from the DSM-IV, are valid in the search

for genetic aetiology. Currently, available diagnostic

schemes and clinical symptoms have no proven biological

and/or genetic validity. As already raised by Leboyer et al.

(1998), the question is: do our modern definitions of clinical

syndromes (presently considered as phenotypes) accurately

reflect underlying genetic substrates (genotypes)? In a

recent review, Stoltenberg and Burmeister (2000) illustrate

that diagnostic categories may not accurately reflect the

underlying genetic condition with the velo-cardiofacial

syndrome (VCFS). This syndrome is usually caused by a

specific deletion on chromosome 22, and is associated with

comorbid psychiatric disorders, such as schizophrenia,

BPAD or UPAD. The authors conclude that at least some

genetic defects predispose to psychiatric disorders that do

not fall into a clearly defined DSM-IV category. Other

limitations are the locus heterogeneity which implies that

multiple disease genes may be acting with different genes

being implicated in different individuals, and the allelic

heterogeneity that indicates that multiple alleles at a single

disease locus may be implicated in the development of the

disorder and no one allele type alone is thus necessarily

related to the disease (Souery et al., 2001a). It is finally

important to note that the genetic transmission of AD may

involve mitochondrial genome, which would indicate a

maternal mode of transmission.

In order to improve the genetic studies, several authors

have proposed to develop innovative approaches based on

more accurate phenotypic definitions. On the other side,

there is also a considerable need for improving molecular

genetic techniques and methods, looking more carefully at

gene–gene and gene–environment interactions. We propose

here a short summary on promising methods.

7.1. Search for phenotypes in affective disorders

As suggested by Kidd and Matthysee (1978), molecular

genetic approaches should help in refining nosological

categories. However, initial genetic studies have focused

on broad phenotypic definitions, for example, affective

disorders or schizophrenia. Facing the heterogeneity of

results, it has been hypothesized that genetic factors could

explain some symptoms or clinical features of the syn-

dromes, such as severity of the disease, age at onset or

gender predominance. This method has been successfully

used in several somatic diseases. For example, the glyco-

gen-associated protein phosphatase 1 (PP-1) gene has

shown association in early diagnosed diabetes II, but not

with diabetes in general (Doney et al., 2003). In psychiatric

diseases, age at onset or disease severity has been found to

delineate more homogeneous subtypes (subphenotypes).

Among other, suicidal behavior has been considered as a

subphenotype genetically determined. Adoption and family

studies have confirmed the genetic implication in suicide

(Turecki, 2001). Linkowski et al. (1985) reported that 17%

of 713 depressed patients had a first- or second-degree

relative who had committed suicide. Nielsen et al. (1994,

1998) first reported an association between history of

suicide attempt and TPH gene. Bellivier et al. (1998)

examined TPH polymorphism in 152 patients with BPAD

and 94 normal controls. They found an association between

this polymorphism and suicidal behavior in BPAd patients.

Souery et al. (2001b) published data on a large sample of

927 patients with AD from several European populations in

a multicenter project. They observed that the CC genotype

in the A218C polymorphism was less frequent in the

subgroup of UPAD patients with a history of suicide attempt

compared to control subjects. In a recent meta-analysis,

Bellivier et al. (2004) found an overall association between

TPH and suicidal behavior. Bellivier et al. (1997) found no

association between an allele of the 5-HTT gene and suicide

attempts in BPAD patients. They later observed a significant

difference in 5-HTT allele distributions between patients

with AD who had made violent suicide attempts and

controls (Bellivier et al., 2000). Russ et al. (2000) found

no association in 5-HTT polymorphisms between a group of

suicidal patients and controls. In post-mortem studies, an

association was reported by Du et al. (1999). They found a

significantly higher frequency of the 5-HTT gene long allele

in depressed suicide victims compared with matched con-

trols. Bondy et al. (2000) showed a possible association of

the short allele of 5-HTT in patients with violent suicide.

Recently, Courtet et al. (2004) suggested that 5-HTT is

associated with further suicide attempts among patients who

have previously attempted suicide.

Early-onset, and more specifically pediatric-onset, psy-

chiatric disorders have been suggested to have their own


pattern of genetic susceptibility factors. Family studies have

consistently found a higher rate of BPAD among the relatives

of early-onset BPAD patients than in relatives of later-onset

cases (Faraone et al., 2003). Here also, 5-HTT and MAOA

polymorphisms have been explored (Ospina-Duque et al.,

2000; Craddock et al., 2001). In pediatric-onset BPAD,

arguments have been put forward to support an anticipation

phenomenom (Vincent et al., 2000). On the other side, adult-

onset AD begins to focus interest (Kennedy et al., 2003).

Another strategy is to search for more specific neuro-

physiologic, neuroimaging, neurocognitive or neurochemi-

cal trait measures that might identify homogeneous groups

of patients. These ‘‘traits’’ are called ‘‘endophenotypes’’ and

are believed to represent the genetic liability of the disorder

among non-affected subjects (Leboyer et al., 1998). As

suggested by Gottesman and Gould (2003), criteria for

endophenotypes are (i) the trait is associated with the

disease in the population, (ii) it is heritable, (iii) it is not

state-dependent, (iv) it cosegregates with the illness within

families, and (v) it is found in nonaffected family members

at a higher rate than in the general population. Endopheno-

type studies have been highly developed in schizophrenia,

such as eye tracking, working memory, measures of neuro-

physiological response to various stimuli and evoked poten-

tials (Kennedy et al., 2003). Endophenotypes in AD are

more difficult to define. However, some studies have

focused on imaging as a marker of BPAD or UPAD. For

example, a recent work has studied the impact of 5-HTT on

the hippocampal volume in UPAD (Frodl et al., 2004).

Based on the well-studied link between the hippocampus

and mood, the authors have shown that the 5-HTT L-allele

is associated with decreased hippocampal volumes in UPAD

patients, as opposed to healthy controls. Future studies will

have to confirm the hypothesis that a genetic variant might

be related to an endophenotype, maybe transnosographical,

and not specifically to a clinical entity.

7.2. Improving genetic techniques and methods

Recent advances in technology have permitted to devel-

op genetic techniques that could screen several candidate

genes in a limited time. Microarrays constitute a promising

high-throughput method, allowing to screen the expression

of thousands of genes within specific tissues in a relatively

short period of time (Shoemaker and Linsley, 2002). Basi-

cally, microarray is able to monitor the collection of mRNA

in the cell (Bunney et al., 2003). Microarray technique is

based on the hypothesis that changes in mRNA expression,

directly linked to protein activity, can result in phenotypical

and morphological differences. The microarray technology

implies the availability of high quality tissue. For psychiat-

ric disorders, the acquisition, characterization and process-

ing of tissue are fundamental and are discussed elsewhere

(Bunney et al., 2003). Microarray, which has also been

applied to animal models, may be considered as the first step

to detect vulnerability genes, which also includes genome

wide-scans, linkage and association studies. Kakiuchi et al.

(2003) recently applied this process to find that XBP1 gene

(on chromosome 22), implicated in endoplasmic reticulum

stress response signalling, can be considered as a vulnera-

bility factor in BPAD. DNA Microarray was first used in

lymphoblastoid cells from discordant monozygotic twins

with respect to BPAD. XBP1, among others, was identified

in this first step. The next step was to identify a single

nucleotide polymorphism (SNP) within the XBP1 upstream

region. This SNP was studied in a case-control association

study, involving 197 BPAD patients and 451 controls, and

was found to be associated to BPAD. This kind of strategy,

combining microarray and association studies, will have to

be generalized in the future. Microarray can be considered

as one of the functional genomics approaches, gathering a

set of technologies and strategies directed at the problem of

determining the function of genes, and understanding how

the genome works together to generate whole patterns of

biological function (Shilling and Kelsoe, 2002).

Finally, there is considerable need to take into account

environmental factors in genetic studies , such as life stress

and others, since it is accepted that AD are multifactorial

diseases, involving both genetic and environmental factors.

The gene–environment interaction was studied by Caspi et

al. (2003) in a prospective-longitudinal study of a represen-

tative birth cohort, involving subjects assessed nine times

between ages 3 to 26 years. Stressful life events were

systematically screened. In addition, DNA was extracted

for 5-HTT genotyping. A moderated regression framework

was used to test the association between depression and (i)

5-HTT genotype, (ii) stressful life events and (iii) their

interaction. The authors found that the 5-HTT polymor-

phism moderated the influence of stressful life events on

depression. This study provides evidence for a gene/envi-

ronment interaction and implies that environmental factors

might be evaluated in future genetic studies.

8. Ethical considerations

Ethical questions arise from genetic research on complex

diseases, such as AD, as well from clinical management of a

complex disorder, involving both genetic and environmental

components. The approaches and ethical rules on genetic

studies vary between countries, as is the case for the informed

consent (Shore, 1993). The Department of Health andHuman

Services Office for Protection from Research Risks (OPRR)

released a few years ago an evaluation on human subjects

issues in a study at the University of California at Los

Angeles (US) involving outpatients with schizophrenia. Sev-

eral faults with the informed consent documents were found.

In particular, some investigators estimated that people who

have mental disorders should be considered incapable of

providing valid informed consent. This opinion is not cur-

rently accepted in many countries. In a NIMH consensus, it

has been established that consent documents, and the process


by which informed consent is obtained, are state-of-the-art

(Shore, 1996). Parker (2002) recently summarized the diffi-

culties in the enrolment of patients with BPAD. The study of

bipolar disorders presents particular challenges because of

the uncertainty and stigma that surrounds the disorders and

because some of the relevant subjects may have diminished

capacity to consent to participation. During a severe manic or

a depressive episode, the subject will not be able to correctly

judge the cost and benefits of the study. Therefore, inves-

tigators must wait to approach the patient when his symptoms

are controlled by medication. Furthermore, genetic studies do

not offer direct benefit to the patient. This point must be taken

into account and explained to the patient. The disclosure of

familial genetic information has been widely discussed. The

clinician has often to decide when or whether an ethical duty

to inform at-risk family members about an increased genetic

risk overrides the duty to maintain patient confidentiality

(Lehmann et al., 2000). Recently, the American Society of

Human Genetics argued that confidentiality can be breached

in situations in which ‘‘serious and foreseeable harm’’ is

highly likely to occur to the at-risk relative, assuming that the

relative is identifiable and the disease is preventable, treatable

or can be detected in its early stages (American Society of

Human Genetics, 1998). In BPAD, some individuals who

have never considered themselves as affected may be found

to fit the diagnostic criteria. From our experience, it appears

that the clinicians must be aware that the disclosure of such an

information has psychosocial implications for the subjects

and his family. More generally, the clinicians must take time

to explain the nature of the genetic risk, the virtual risk within

the family and the psychosocial consequences.

9. Conclusion

The amazing developments in molecular genetics during

the last decade made possible the search for susceptibility

genes in AD. Nevertheless, results so far remain preliminary

in both linkage and association studies. The growing eluci-

dation of biochemical pathways implicated in AD will

provide new candidate genes to be tested. Advances in the

definition of disease phenotypes and the identification of

endophenotypes will certainly be helpful in the future.

Finally, the application of modern technology to global

studies, involving both clinical and environmental factors,

is predictive of an optimistic era of discovery of suscepti-

bility genes of AD.

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Molecular genetics of affective disorders

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