Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

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Abstract

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

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PLINK: a tool set for whole-genome association and population-based linkage analyses.

Shaun Purcell, Benjamin M. Neale, Kathe E. O. Todd-Brown … (2007)

Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

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Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.

Neil Walker, Peter Holmans (2007)

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

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XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance.

R. A. FISHER (1919)

Several attempts have already been made to interpret the well-established results of biometry in accordance with the Mendelian scheme of inheritance. It is here attempted to ascertain the biometrical properties of a population of a more general type than has hitherto been examined, inheritance in which follows this scheme. It is hoped that in this way it will be possible to make a more exact analysis of the causes of human variability. The great body of available statistics show us that the deviations of a human measurement from its mean follow very closely the Normal Law of Errors, and, therefore, that the variability may be uniformly measured by the standard deviation corresponding to the square root of the mean square error. When there are two independent causes of variability capable of producing in an otherwise uniform population distributions with standard deviations σ 1 and σ 2 , it is found that the distribution, when both causes act together, has a standard deviation . It is therefore desirable in analysing the causes of variability to deal with the square of the standard deviation as the measure of variability. We shall term this quantity the Variance of the normal population to which it refers, and we may now ascribe to the constituent causes fractions or percentages of the total variance which they together produce. It is desirable on the one hand that the elementary ideas at the basis of the calculus of correlations should be clearly understood, and easily expressed in ordinary language, and on the other that loose phrases about the “percentage of causation,” which obscure the essential distinction between the individual and the population, should be carefully avoided.

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Author and article information

Journal

Title: Nature

Abbreviated Title: Nature

Publisher: Springer Science and Business Media LLC

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Created: August 2009

Publication date (Electronic): July 1 2009

Publication date (Print): August 2009

Volume: 460

Issue: 7256

Pages: 748-752

Article

DOI: 10.1038/nature08185

PMC ID: 3912837

PubMed ID: 19571811

SO-VID: 9dc22146-2c53-4f0e-a972-4c39356d37ad

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http://www.springer.com/tdm

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