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The Meta-Analysis of Genetic Studies
Published in Christopher H. Schmid, Theo Stijnen, Ian R. White, Handbook of Meta-Analysis, 2020
Cosetta Minelli, John Thompson
There is a long-standing debate in genetic epidemiology over whether most common diseases are caused by a small number of common genetic variants; the so-called common-disease common-variant hypothesis (Smith and Lusis, 2002). It was originally thought that a few common variants with relatively large effects would be responsible for most of the genetic heritability of common disease, but the reality uncovered by GWAS has proved to be much more complicated. For example, investigations of the genetics of height have shown that larger and larger studies find more and more variants with smaller and smaller effects (Wood et al., 2014). Improved technology will soon make it economic to sequence the entire genome of every participant so that we will be able to search for rare variants, which would never be included on a GWAS chip. Emphasis on rare variants will make meta-analysis even more important (see Section 17.2.7).
Genetic contributions to neurodevelopmental disorders
Published in Anna L. Barnett, Elisabeth L. Hill, Understanding Motor Behaviour in Developmental Coordination Disorder, 2019
This newfound knowledge regarding the diverse effects of genetic variation upon disease has caused many researchers to revisit the way in which genetic disorders are modelled. Prior to the Human Genome Project, it was largely thought that most genetic diseases could be modelled as Mendelian traits in which high impact changes in one (dominant) or two (recessive) copies of a given gene were necessary and sufficient to cause disease. These diseases tend to be rare in populations as the mutations that cause them are subject to negative selective pressure. In contrast, common disorders, were considered to be the extreme of normal distributions (e.g. hypertension, language impairment) and were modelled to involve interactions between 3 and 10 common genetic variants and environmental factors. In these genetically complex disorders, the variants themselves do not cause disease but instead act as risk factors that increase the chances of impairment. Independently, each variant has only a small effect upon disorder risk and so is less constrained and relatively common in a given population; the common disease, common variant hypothesis (Lander, 1996; Reich & Lander, 2001).
A Genetic Framework for Addiction
Published in Hanna Pickard, Serge H. Ahmed, The Routledge Handbook of Philosophy and Science of Addiction, 2019
Philip Gorwood, Yann Le Strat, Nicolas Ramoz
The genetics of addictive disorders is probably complex, and could be oligogenic (few genes are involved) or polygenic (many genes are significantly involved), or, in only rare exceptions, it may have a monogenic origin (one gene only). There are two human genetic models that explain how each gene or locus (a specific region of the genome) can impact the risk of a complex disorder such as addictive disorders. These models are called “common disease/common variant” (CDCV) and “multiple rare variants” (MRV) (Figure 22.1). Together they form the allelic spectrum that could explain the continuum of patients with addictive disorder. The CDCV model puts forward common genetic variants (allelic frequency >5%) that confer a modest genetic relative risk (≤1.5) toward developing a complex trait. The MRV model proposes that many different rare genetic variants (frequency ≤1%) confer a very strong genetic relative risk (≥10) toward developing a complex trait. The rare variants (and rare effects) are very difficult to identify because they require the screening of hundreds of thousands of subjects.
Polygenic risk scores for predicting outcomes and treatment response in psychiatry: hope or hype?
Published in International Review of Psychiatry, 2022
Laura Fusar-Poli, Bart P. F. Rutten, Jim van Os, Eugenio Aguglia, Sinan Guloksuz
Decades of twin, family, and adoption studies have established that mental disorders aggregate in families and are substantially heritable (Smoller et al., 2019). Molecular genetics studies have been previously restricted to a limited set of ‘candidate genes’ that are selected based on biological hypotheses about putative etiopathology, with a vast overestimation of the effect size that such loci were likely to have. However, the genetics of mental disorders appear to be far more complex, as was first postulated more than 50 years ago: the polygenic theory of schizophrenia (Gottesman & Shields, 1967). According to this theory, each individual in the general population has varying degrees of quantifiable genetic and environmental liability for schizophrenia but develops schizophrenia only when the combined liability exceeds the threshold on the continuum. More recently, the common disease-common variant (CDCV) hypothesis argued that numerous common genetic variants of very small individual effects would substantially contribute to genetic susceptibility to common disorders (Reich & Lander, 2001).