title: Fast Principal-Component Analysis Reveals Convergent Evolution of ADH1B in Europe and East Asia.
abstract: Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude. We apply FastPCA to a cohort of 54,734 European Americans, identifying 5 distinct subpopulations spanning the top 4 PCs. Using the PC-based test for natural selection, we replicate previously known selected loci and identify three new genome-wide significant signals of selection, including selection in Europeans at ADH1B. The coding variant rs1229984(∗)T has previously been associated to a decreased risk of alcoholism and shown to be under selection in East Asians; we show that it is a rare example of independent evolution on two continents. We also detect selection signals at IGFBP3 and IGH, which have also previously been associated to human disease.
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: galinsky@fas.harvard.edu.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Galinsky
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatia
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Po-Ru
authors.initials: PR
authors.lastname: Loh
authors.affiliation: Google, Palo Alto, CA 94043, USA.
authors.forename: Stoyan
authors.initials: S
authors.lastname: Georgiev
authors.affiliation: Departments of Statistical Science, Computer Science, and Mathematics, Duke University, Durham, NC 27708, USA.
authors.forename: Sayan
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Patterson
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aprice@hsph.harvard.edu.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D005060:Europe; D019143:Evolution, Molecular; D005202:Asia, Eastern; D056426:Genetic Loci; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D008957:Models, Genetic; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D012641:Selection, Genetic; D044465:White People / Q000235:genetics*
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase