Candidate genes vs. whole genome search

Heritability, defining the proportion of the variance explained by genetic factors in certain phenotypes (traits or symptoms), is estimated by comparing the concordance rates of monozygotic and dizygotic twin pairs (Glatt et al., 2008). To identify the specific genes accounting for the heritability, two major methods are currently applied that supplement each other. Candidate gene analyses can reveal the actual genetic variants of the protein-coding genes that are implicated in the pathophysiology of the disorder (Glatt et al., 2008). Based on neurobiological theories, polymorphisms in the monoamine (dopamine, norepinephrine, and serotonin) receptor and transporter genes are the most widely studied candidate genes in psychiatric genetics. The alternative strategy aims to identify specific chromosomal regions that are related to the disorder by analyzing the whole genome without an a priori hypothesis. Linkage studies analyze marker polymorphisms throughout the genome in extended pedigrees of patients to find chromosomal region(s) linked to the disorder. A major genetic effect is identified as a cosegregation of a marker variant (allele) and the disorder with a logarithm of odds (LOD) score of higher than 3 (Lander and Kruglyak, 1995). Whereas this strategy is highly powerful for monogenic diseases, it has proven less effective for complex inheritance disorders in which the individual genetic factors have small effects. Genome-wide association studies (GWAS) are a recent approach of whole genome searches. These studies aim to identify common genetic variants with a relative risk of 1.1 to 1.4 by studying thousands of patients and control subjects (Cichon et al., 2009). Because single studies using either approach cannot identify definite genetic risk alleles unambiguously, meta-analyses combine the samples to gain a higher power of analysis. Among childhood-onset disorders, ADHD and autism have been assessed by GWAS, resulting in numerous novel putative candidate genes (Franke et al., 2009; Weiss, 2009), and the first GWAS in obsessive compulsive disorder (OCD) and TS are presently underway (Grados, 2010). Although the first meta-analysis of ADHD GWAS has not been able to identify any significant genome-wide association (Neale et al., 2010), the conclusion is probably just as important: If common genetic variants account for the majority of the genetic component in the pathogenesis of a disorder, then their effect sizes must be very small. The alternative explanation would be that mostly rare genetic variants (different in every patient but might effect the same neurobiological pathway) account for the heritable component. A new concept for future genetic studies emphasizes the underlying traits in psychiatric disorders which can be expressed as variations in brain functioning. Certain gene variants influence the traits and not the disorder. The risk to develop a disorder comes from the combination of these traits (Hudziak and Faraone, 2010). Therefore, in this review, we mention not only the categorical, psychiatric disorder based association studies (third section), but also those genetic association studies which used quantitative traits (fourth section). Wherever possible, gene × gene interaction findings are indicated, to illustrate the complexity of the genetic background in more details.

Among the candidate gene analyses of childhood-onset psychiatric disorders, family-based studies are preferred over the simple case-control design, because these methods are devoid of population stratification problems (Schulze and McMahon, 2002), and biological parents are often easily accessible. For example, the Transmission Disequilibrium Test measures the transmission rates of two different alleles from heterozygous parents to the affected offspring; if a significant over-transmission of an allele is observed, that genetic variant can be linked to the disorder. Most of the family-based studies apply diagnostic categories, usually by the DSM-IV (American Psychiatric Association, 1994), which is used in the United States, and sometimes by the ICD-10 (World Health Organization, 1993), which is used in the clinical practice of European countries. At the early onset disorders (ADHD, TS, and OCD sections) we mention specifically whenever family-based association tests were used. At the other sections, the conducted studies follow either the case-control design (categorical approach, third section) or the dimensional approach (fourth section).

In this review, we focus on functional polymorphisms, where the different alleles have been shown to have altered molecular functions. Hitherto, mostly common genetic variants (minor allele frequency higher than 5%) have been studied in psychiatric genetics. To achieve a high frequency in a certain population, a genetic polymorphism needs to either be neutral or favorable in the actual environmental circumstances. Because the surrounding environment can change rapidly, favorable genetic variants might become unfavorable ones. An interesting example is the widely-investigated 7-repeat allele of the dopamine D4 receptor gene that was reported as a young genetic variation, which increased to high frequency in human populations by positive selection (Ding et al., 2002). However, this allele is now implicated as a genetic risk factor for dopamine-related psychiatric disorders. This example underlines the importance of talking about gene variants influencing certain traits (e.g., impulsivity), and not genetic risk factors for psychiatric disorders (e.g., ADHD or substance abuse).

Another important issue worthwhile mentioning is that certain genetic constellations can make individuals more susceptible or more resilient to environmental factors. Mostly prenatal, postnatal, and childhood adverse effects of the physical and social environment have been implicated in gene × environment interactions leading to development of psychiatric disorders (Wermter et al., 2010). Although the majority of these interaction results have not been convincingly replicated, we mention them at the genetic finding sections, because this type of analyses will gain increasing significance in future genetic studies.

Date: 2016-01-03; view: 871