After GWAS: Searching for Genetic Risk for Schizophrenia and Bipolar Disorder

Abstract

Ten years ago it was widely expected that the genetic basis of common disease would be resolved by genome-wide association studies (GWAS), large-scale studies in which the entire genome is covered by genetic markers. However, the bulk of heritable variance remains unexplained. The authors consider several alternative research strategies. For instance, whereas it has been hypothesized that a common disease is associated primarily with common genetic variants, it is now plausible that multiple rare variants each have a potent effect on disease risk and that they could accumulate to become a substantial component of common disease risk. This idea has become more appealing since the discovery that copy number variants (CNVs) are a substantial source of human mutations and are associated with multiple common diseases. CNVs are structural genomic variants consisting of microinsertions, microdeletions, and transpositions in the human genome. It has been argued that numerous rare CNVs are plausible causes of a substantial proportion of common disease, and rare CNVs have been found to be potent risk factors in schizophrenia and autism. Another approach is to "parse the genome," i.e., reanalyze subsets of current GWAS data, since the noise inherent in genome-wide approaches may be hiding valid associations. Lastly, technological advances and declining costs may allow large-scale genome-wide sequencing that would comprehensively identify all genetic variants. Study groups even larger than the 10,000 subjects in current meta-analyses would be required, but the outcomes may lead to resolution of our current dilemma in common diseases: Where is the missing heritability?

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Most recent evidence supports a combination of genetic and environmental factors contributing to the development of the disorder (Marenco and Weinberger, 2000). To date, no one gene, single-nucleotide polymorphism, or mutation has been consistently linked to the illness, and it is likely that multiple susceptibility genes create a predisposition to developing schizophrenia (Fanous et al, 2012;Gershon et al, 2011;Levinson et al, 2012). Genetics studies, which have led the way for diseases such as breast cancer and cystic fibrosis, have been much less impactful in the schizophrenia field.…”

Associação entre polimorfismos genéticos e transtorno bipolar

“…Is now plausible that multiple rare variants each have a potent effect on disease risk and that they could accumulate to become a substantial component of mental disease risk 44 . The search for genetic information that are associated with the outbreak of TB involves structural and environmental factors.…”

Genetics of Schizophrenia and other Psychotic Disorders

“…In the long term the aim will be to undertake studies similar to GWAS with very large sample sizes [113]. Until sequencing technology is inexpensive enough to perform these large sample studies various approaches have been suggested to further our understanding.…”