title: Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data.
abstract: Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel.
authors.affiliation: Department of Biostatistics, University of California, Los Angeles, California, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Texas, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, California, United States of America.|Department of Epidemiology, University of California, Los Angeles, California, United States of America.
authors.forename: Kei-Hang K
authors.initials: KK
authors.lastname: Chan
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, California, United States of America.|Department of Biomathematics, University of California, Los Angeles, California, United States of America.|Department of Statistics, University of California, Los Angeles, California, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lange
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, California, United States of America.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
mesh_terms: D008040:Genetic Linkage; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci; D012984:Software
keywords: fixed-effects models; genome-wide association study; kinship; multivariate traits; pedigree; score test