Swedish twin registry, N >30,000

Bulik et al. 2006 Bulik et al. 2000 (review) Tyndale 2003 (review)

Nicotine addiction Antisocial personality disorder

0.4-0.7 Li 2003; Tyndale 2003 (reviews)

0.32 51 studies Rhee and Waldman 2002 (meta-analysis)

Genetic epidemiology can also contribute to the exploration of more complex questions, such as whether genetic risk factors are shared among different psychiatric disorders and gender and whether they can moderate the effects of environmental risk factors (Kendler 2001) and can thus lead the design of follow-up molecular genetic studies. For example, a twin study has suggested that genetic risk factors for major depression could in part act by increasing vulnerability to stressful life events (Kendler 1995). This finding has been corroborated in recent years by the now well-replicated interaction of functional alleles of the locus encoding the serotonin transporter protein with stressful life events to predict depression (Caspi et al. 2003; Kaufman et al. 2004; Kendler et al. 2005; Sjoberg et al. 2006; Surtees et al. 2006; Wilhelm et al. 2006). Genetic epidemiological and more specifically twin studies have therefore been an important foundation of psychiatric genetics and are likely to continue to contribute more elaborate disease models for future molecular genetic analysis. The major limitation of these studies, however, is that the estimated heritability using twin studies is only an estimate of the aggregate genetic effect. Heritability does not give information on the contributions of specific genes to risk for a disorder. These questions, the answers to which ultimately will shed light on the underlying developmental neurobiology underlying psychiatric illness, require molecular genetic methods.

Psychiatric Disorders Are Complex Genetic Disorders

Genetic epidemiological studies have also established that psychiatric disorders are likely not single-gene disorders inherited in a Mendelian fashion (i.e., in a clear recessive, dominant, or X-linked fashion), although rare families in which psychiatric phenotypes are inherited this way have been reported (Brunner et al. 1993). A genetic disorder can be complex for several reasons:

■ Incomplete penetrance. Not everybody carrying the disease allele(s) becomes ill.

■ Phenocopy. Individuals, even within the same families, can exhibit similar or identical traits because of environmental factors.

■ Locus heterogeneity. Variants in different genes can lead to similar or identical disease phenotypes.

■ Allelic heterogeneity. Different patterns of variation within the same gene or genes can lead to similar or identical disease phenotypes.

■ Polygenic inheritance. Additive or interactive effects of variation at multiple genes (i.e., epistatic effects) are necessary for an illness to manifest.

■ Gene-environment interaction. A disorder manifests in response to environmental factors only in the context of predisposing genetic variants. An extreme example of such interaction is phenylketonuria, where exposure to dietary phenylalanine causes severe neurobehavioral impairment in individuals carrying two mutant copies of the locus encoding phenylalanine hydroxylase; limitation of dietary phenylalanine prevents the neurobehavioral disorder.

■ High frequency of the disorder and the predisposing alleles. It appears increasingly likely that common disorders such as schizophrenia, diabetes mellitus, stroke, or hypertension represent final common outcomes to a variety of combinations of environmental and genetic predisposing factors. Thus, two individuals, even within the same family, might manifest clinically indistinguishable disorders for different reasons.

■ Other genetic mechanisms of inheritance. Alternative genetic mechanisms—for example, mitochondrial inheritance or alteration of the genome across generations, such as occurs in trinucleotide-repeat-expansion disorders (e.g., Huntington's disease, fragile X syndrome) or in epigenetic disorders—may be operable in producing a disorder. Epigenetic disorders result from alterations in the genetic material that do not involve changes in the base pair sequence of DNA. Examples of epigenetic disease include the imprinted disorders Angelman syndrome and Prader-Willi syndrome, in which parent-of-origin-dependent chemical modification of DNA produces different phenotypic outcomes from the same chromosomal deletion. Newton and Duman recently reviewed possible roles of epigenetic mechanisms in the action of psychotropic drugs (Newton and Duman 2006) and in neuronal plasticity (Duman and Newton 2007).

From the cumulative evidence of psychiatric genetic studies so far, one can conclude that psychiatric disorders best fit a polygenic mode of inheritance, with two or more polymorphic loci contributing to these disorders, including unipolar depression (Johansson et al. 2001; Kendler et al. 2006), bipolar disorder (Blackwood and Muir 2001), schizophrenia (Sobell et al. 2002), and autism (Folstein and Rosen-Sheidley 2001). However, it is still relatively unclear how many loci contribute to each disorder. The inheritance of schizophrenia, for example, fits models including only a few loci as well as very large numbers of loci (Risch 1990a, 1990b; Sullivan et al. 2003). Data from gene-mapping studies suggest that different loci are indeed likely to contribute to schizophrenia and bipolar disorder in different individuals or families (meta-analyses [Levinson et al. 2003; Lewis et al. 2003; Segurado et al. 2003]), strongly supporting the hypothesis that locus heterogeneity is an important factor in schizophrenia. Thus, Bleuler (1951) appears to have been correct when he referred to dementia praecox as "the group of schizophrenias."

As already noted, susceptibility genes are likely to interact with environment, gender, and other genes, making the search for genes for psychiatric disorders even more complex (Kendler and Greenspan 2006). Twin studies have produced evidence of genetic interactions with stressful life events predicting major depression (Kendler et al. 1995a) and with early rearing environment to predict schizophrenia, conduct disorder, and drug abuse (Cadoret et al. 1995a, 1995b; Tienari et al. 2004). These gene-environment interactions have now been substantiated by several molecular genetic studies (e.g., Binder et al. 2008; Bradley et al. 2008; Caspi et al. 2002, 2003, 2005), suggesting that future genetic and genomic studies will need to include analysis of both sets of factors. Furthermore, it is likely that there are gender-specific predisposing genes for psychiatric disorders. Data from twin studies suggest that the combined genetic factors predisposing to major depression, phobias, and alcoholism may differ in some respects for men and women (Kendler and Prescott 1999; Kendler and Walsh 1995; Kendler et al. 2001a, 2002, 2006; Prescott and Kendler 2000; Prescott et al. 2000), and this has been supported in molecular genetic studies by the identification of gender-specific loci for major depression (e.g., Abkevich et al. 2003; Zubenko et al. 2002). Finally, gene-gene interactions may be relevant for these disorders (Risch 1990b).

Response to Drug Treatment

In contrast to disease susceptibility, genetic epidemiological studies on responses to psychotropic drugs are rare. There is some evidence from family studies that suggests an important contribution of genetic factors in antidepressant response. Already in the early 1960s, studies on the effects of tricyclic antidepressants (TCAs) in relatives suggested that response to these drugs was similar among family members (Angst 1961; Pare et al. 1962). O'Reilly et al. (1994) reported a familial aggregation of response to tranylcypromine, a monoamine oxidase inhibitor, in a large family with major depression. These initial reports were followed by only a few systematic studies. Franchini et al. (1998) indicated a possible genetic basis of response to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in 45 pairs of relatives. In light of these data, some groups have used or proposed to use response to certain antidepressant drugs or mood stabilizers as an additional phenotype in classical linkage analyses for mood disorders in the hope of identifying genetically more homogeneous families (Serretti et al. 1998; Turecki et al. 2001).

Nonetheless, family studies supporting a genetic basis of response to psychotropic drugs are sparse, certainly reflecting the extreme difficulties inherent in conducting well-controlled family studies of therapeutic responses to medications. It has been proposed that genetic modifiers for response to treatment to psychotropic drugs may be easier to detect than associations with disease susceptibility, as the genetic contribution to these traits may be less complex (Weinshilboum 2003). So far, the data are insufficient to support or refute that contention.

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