Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies

There is strong evidence that rare variants are involved in complex disease etiology. The first step in implicating rare variants in disease etiology is their identification through sequencing in both randomly ascertained samples (e.g., the 1,000 Genomes Project) and samples ascertained according to disease status. We investigated to what extent rare variants will be observed across the genome and in candidate genes in randomly ascertained samples, the magnitude of variant enrichment in diseased individuals, and biases that can occur due to how variants are discovered. Although sequencing cases can enrich for casual variants, when a gene or genes are not involved in disease etiology, limiting variant discovery to cases can lead to association studies with dramatically inflated false positive rates.

[1]  Jonathan C. Cohen,et al.  Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Richard R. Hudson,et al.  Generating samples under a Wright-Fisher neutral model of genetic variation , 2002, Bioinform..

[3]  M. Hayden,et al.  Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. , 2006, Annual review of nutrition.

[4]  Chiara Sabatti,et al.  Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. , 2006, Human molecular genetics.

[5]  R. Service.  The Race for the $1000 Genome , 2006, Science.

[6]  N. Siva.  1000 Genomes project , 2008, Nature Biotechnology.

[7]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[8]  Jonathan C. Cohen,et al.  Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol , 2004, Science.

[9]  B. Kerem,et al.  Cystic fibrosis in Jews: frequency and mutation distribution. , 1997, Genetic testing.

[10]  J. Pritchard.  Are rare variants responsible for susceptibility to complex diseases? , 2001, American journal of human genetics.

[11]  M. King,et al.  Inherited breast and ovarian cancer. , 1995, Human molecular genetics.

[12]  L. Cardon,et al.  Population stratification and spurious allelic association , 2003, The Lancet.

[13]  Roded Sharan,et al.  Medical sequencing at the extremes of human body mass. , 2006, American journal of human genetics.

[14]  M. Spitz,et al.  Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. , 2008, American journal of human genetics.

[15]  M. King,et al.  Inherited breast and ovarian cancer. What are the risks? What are the choices? , 1993, JAMA.

[16]  Hongyu Zhao,et al.  Rare independent mutations in renal salt handling genes contribute to blood pressure variation , 2008, Nature Genetics.

[17]  Noah A Rosenberg,et al.  Mathematical properties of the r2 measure of linkage disequilibrium. , 2008, Theoretical population biology.

[18]  G. Jones,et al.  Novel rare mutations and promoter haplotypes in ABCA1 contribute to low‐HDL‐C levels , 2008, Clinical genetics.

[19]  Eric Boerwinkle,et al.  Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL , 2007, Nature Genetics.

[20]  Anthony R. Dallosso,et al.  Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. , 2008, Cancer research.

[21]  S. Leal,et al.  Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. , 2008, American journal of human genetics.

[22]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[23]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[24]  P. Donnelly,et al.  The Fine-Scale Structure of Recombination Rate Variation in the Human Genome , 2004, Science.

[25]  J. Pritchard,et al.  The allelic architecture of human disease genes: common disease-common variant...or not? , 2002, Human molecular genetics.

[26]  Francis S Collins,et al.  A HapMap harvest of insights into the genetics of common disease. , 2008, The Journal of clinical investigation.