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Causality and PsychopathologyFinding the Determinants of Disorders and their Cures$
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Patrick Shrout, Katherine Keyes, and Katherine Ornstein

Print publication date: 2011

Print ISBN-13: 9780199754649

Published to Oxford Scholarship Online: November 2020

DOI: 10.1093/oso/9780199754649.001.0001

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PRINTED FROM OXFORD SCHOLARSHIP ONLINE (oxford.universitypressscholarship.com). (c) Copyright Oxford University Press, 2021. All Rights Reserved. An individual user may print out a PDF of a single chapter of a monograph in OSO for personal use. date: 08 December 2021

Rare Variant Approaches to Understanding the Causes of Complex Neuropsychiatric Disorders

Rare Variant Approaches to Understanding the Causes of Complex Neuropsychiatric Disorders

10 (p.252) Rare Variant Approaches to Understanding the Causes of Complex Neuropsychiatric Disorders
Causality and Psychopathology

Matthew W. State

Oxford University Press

The distinction between genetic variation that is present in more than 5% of the population (defined as common) and genetic variation that does not meet this threshold (defined as rare) is often lost in the discussion of psychiatric genetics. As a general proposition, the field has come to equate the hunt for common variants (or alleles) with the search for genes causing or contributing to psychiatric illness. Indeed, the majority of studies on mood disorders, autism, schizophrenia, obsessive–compulsive disorder, attention-deficit/hyperactivity disorder, and Tourette syndrome have restricted their analyses to the potential contribution of common alleles. Studies focusing on rare genetic mutations have, until quite recently, been viewed as outside the mainstream of efforts aimed at elucidating the biological substrates of serious psychopathology. Both the implicit assumption that common alleles underlie the lion’s share of risk for most common neuropsychiatric conditions and the notion that the most expeditious way to elucidate their biological bases will be to concentrate efforts on common alleles deserve careful scrutiny. Indeed, key findings across all of human genetics, including those within psychiatry, support the following alternative conclusions: (1) for disorders such as autism and schizophrenia, the study of rare variants already holds the most immediate promise for defining the molecular and cellular mechanisms of disease (McClellan, Susser, & King, 2007; O’Roak & State, 2008); (2) common variation will be found to carry much more modest risks than previously anticipated (Altshuler & Daly, 2007; Saxena et al., 2007); and (3) rare variation will account for substantial risk for common complex disorders, particularly for neuropsychiatric conditions with relatively early onset and chronic course. This chapter addresses the rare variant genetic approach specifically with respect to mental illness. It first introduces the distinction between the key characteristics of common and rare genetic variation. It then briefly addresses the methodologies employed to demonstrate a causal or contributory role for genes in complex disease, focusing on how these approaches differ in terms of the ability to detect and confirm the role of rare variation.

Keywords:   Alleles, Bilineal inheritance, Candidate gene association studies, Genetic association, Homologous recombination, Linkage studies, Mutation, Neuropsychiatric disorders, Parametric linkage

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