title: A population genetic signal of polygenic adaptation.
abstract: Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of [Q(ST)/F(ST)] comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.
authors.affiliation: Graduate Group in Population Biology, University of California, Davis, Davis, California, United States of America; Center for Population Biology, University of California, Davis, Davis, California, United States of America; Department of Evolution and Ecology, University of California, Davis, Davis, California, United States of America.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Berg
authors.affiliation: Center for Population Biology, University of California, Davis, Davis, California, United States of America; Department of Evolution and Ecology, University of California, Davis, Davis, California, United States of America.
authors.forename: Graham
authors.initials: G
authors.lastname: Coop
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D001827:Body Height / Q000235:genetics; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005787:Gene Frequency; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D016045:Human Genome Project; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D012880:Skin Pigmentation / Q000235:genetics
references.citation: Nature. 2010 Jun 3;465(7298):627-31
references.pmid: 20336072
references.citation: Hum Genet. 2011 Apr;129(4):407-18
references.pmid: 21188420
references.citation: Genetics. 1997 Apr;145(4):1229-41
references.pmid: 9093871
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references.pmid: 22243964
references.citation: PLoS Biol. 2013 Sep;11(9):e1001661
references.pmid: 24068893
references.citation: PLoS Genet. 2008 Feb;4(2):e32
references.pmid: 18282109
references.citation: Am Nat. 1998 Mar;151(3):283-92
references.pmid: 18811359
references.citation: Nature. 2012 Nov 1;491(7422):119-24
references.pmid: 23128233
references.citation: Evolution. 2014 Feb;68(2):559-68
references.pmid: 24117061
references.citation: PLoS Genet. 2011 Jan 06;7(1):e1001266
references.pmid: 21253569
references.citation: Ann Hum Genet. 2007 May;71(Pt 3):354-69
references.pmid: 17233754
references.citation: Cold Spring Harb Symp Quant Biol. 1964;29:9-20
references.pmid: 14278497
references.citation: Nature. 1991 Jun 20;351(6328):652-4
references.pmid: 1904993
references.citation: PLoS One. 2012;7(7):e40964
references.pmid: 22848416
references.citation: Genetics. 2013 Mar;193(3):929-41
references.pmid: 23307896
references.citation: Nat Genet. 2012 Sep;44(9):981-90
references.pmid: 22885922
references.citation: Genetics. 2008 Jun;179(2):1135-41
references.pmid: 18558659
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8962-8
references.pmid: 20445093
references.citation: Genome Res. 2005 Nov;15(11):1566-75
references.pmid: 16251466
references.citation: PLoS Genet. 2013 Jun;9(6):e1003566
references.pmid: 23785302
references.citation: PLoS Genet. 2013;9(7):e1003608
references.pmid: 23874214
references.citation: Genetics. 1983 Dec;105(4):985-1002
references.pmid: 17246186
references.citation: PLoS Genet. 2013;9(2):e1003264
references.pmid: 23408905
references.citation: Nat Genet. 2012 Sep;44(9):1015-9
references.pmid: 22902787
references.citation: Genome Res. 2009 May;19(5):826-37
references.pmid: 19307593
references.citation: Science. 2008 Feb 22;319(5866):1100-4
references.pmid: 18292342
references.citation: BMC Bioinformatics. 2013 Apr 19;14:132
references.pmid: 23601181
references.citation: Am J Hum Genet. 1962 Dec;14:353-62
references.pmid: 13937884
references.citation: Evolution. 2008 Jun;62(6):1437-49
references.pmid: 18346219
references.citation: Nat Genet. 2007 Feb;39(2):218-25
references.pmid: 17206141
references.citation: Genetics. 2012 Dec;192(4):1503-11
references.pmid: 23023004
references.citation: Nat Genet. 2005 Aug;37(8):868-72
references.pmid: 16041375
references.citation: PLoS Genet. 2013 May;9(5):e1003447
references.pmid: 23717210
references.citation: Nat Genet. 2010 Nov;42(11):937-48
references.pmid: 20935630
references.citation: J Evol Biol. 2007 Jan;20(1):1-8
references.pmid: 17209986
references.citation: Nature. 2013 Feb 14;494(7436):234-7
references.pmid: 23376951
references.citation: Nat Genet. 2004 Nov;36(11 Suppl):S54-60
references.pmid: 15508005
references.citation: Genetics. 2009 Nov;183(3):1055-63
references.pmid: 19687138
references.citation: PLoS Genet. 2010 Mar 05;6(3):e1000867
references.pmid: 20221248
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8924-30
references.pmid: 20445095
references.citation: Nat Genet. 2011 Dec 11;44(1):67-72
references.pmid: 22158537
references.citation: Nat Rev Genet. 2010 Jul;11(7):459-63
references.pmid: 20548291
references.citation: Am Nat. 2001 Mar;157(3):245-61
references.pmid: 18707288
references.citation: Mol Ecol. 2008 Apr;17(8):1885-96
references.pmid: 18363667
references.citation: Nature. 2007 Oct 18;449(7164):913-8
references.pmid: 17943131
references.citation: Mol Psychiatry. 2011 Oct;16(10):996-1005
references.pmid: 21826061
references.citation: Evolution. 1992 Apr;46(2):381-389
references.pmid: 28564025
references.citation: Nat Genet. 2013 Nov;45(11):1274-1283
references.pmid: 24097068
references.citation: Nat Genet. 2012 Jun 17;44(7):821-4
references.pmid: 22706312
references.citation: Nature. 2012 Feb 08;482(7384):173-8
references.pmid: 22318601
references.citation: Am J Hum Genet. 2013 Jun 6;92(6):866-81
references.pmid: 23731540
references.citation: Nature. 1992 Apr 9;356(6369):519-20
references.pmid: 1560824
references.citation: Genetics. 1993 May;134(1):369-75
references.pmid: 8514144
references.citation: Appl Transl Genom. 2013 Nov 07;2:78-94
references.pmid: 27896059
references.citation: J Dairy Sci. 2009 Feb;92(2):433-43
references.pmid: 19164653
references.citation: PLoS Genet. 2011 Oct;7(10):e1002298
references.pmid: 21998595
references.citation: Nat Rev Genet. 2010 Dec;11(12):880-6
references.pmid: 21045869
references.citation: Genetics. 2011 Oct;189(2):621-32
references.pmid: 21840853
references.citation: Nat Genet. 2004 Apr;36(4):388-93
references.pmid: 15052270
references.citation: Hum Mol Genet. 2012 Feb 1;21(3):711-20
references.pmid: 22021425
references.citation: Am J Hum Genet. 2006 Apr;78(4):629-44
references.pmid: 16532393
references.citation: Genetics. 2010 Aug;185(4):1411-23
references.pmid: 20516501
references.citation: Genetics. 2010 Sep;186(1):241-62
references.pmid: 20855576
references.citation: Genetics. 1987 May;116(1):153-9
references.pmid: 3110004
references.citation: Genet Res. 1999 Dec;74(3):215-21
references.pmid: 10689799
references.citation: Nat Genet. 2009 May;41(5):527-34
references.pmid: 19396169
references.citation: Nat Genet. 2010 Apr;42(4):348-54
references.pmid: 20208533
references.citation: PLoS Genet. 2009 May;5(5):e1000471
references.pmid: 19424416
references.citation: Hum Mol Genet. 2009 Apr 15;18(R1):R9-17
references.pmid: 19297406
references.citation: J Hum Evol. 2004 Oct;47(4):253-66
references.pmid: 15454336
references.citation: PLoS Genet. 2007 Jun;3(6):e90
references.pmid: 17542651
references.citation: Nat Genet. 2011 Jun;43(6):519-25
references.pmid: 21552263
references.citation: Science. 1996 Sep 13;273(5281):1516-7
references.pmid: 8801636
references.citation: Trends Ecol Evol. 1995 Jun;10(6):248-52
references.pmid: 21237029
references.citation: PLoS Genet. 2012;8(11):e1002967
references.pmid: 23166502
references.citation: Genetics. 2001 Apr;157(4):1819-29
references.pmid: 11290733
references.citation: Genetics. 2013 Sep;195(1):205-20
references.pmid: 23821598
references.citation: BMJ. 2013 Apr 09;346:f1515
references.pmid: 23571838
references.citation: Genet Res. 1997 Oct;70(2):155-74
references.pmid: 9449192
references.citation: Nat Genet. 2013 Jun;45(6):690-6
references.pmid: 23583978
references.citation: Mol Ecol. 2005 Feb;14(2):363-79
references.pmid: 15660931
references.citation: Mol Ecol. 2012 Apr;21(7):1548-66
references.pmid: 22332667
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: Curr Biol. 2010 Feb 23;20(4):R208-15
references.pmid: 20178769
references.citation: Genetics. 2008 Mar;178(3):1709-23
references.pmid: 18385116
references.citation: Annu Rev Anim Biosci. 2013 Jan;1:221-37
references.pmid: 25387018
references.citation: Ann Hum Biol. 2009 Jan-Feb;36(1):74-87
references.pmid: 19085512
references.citation: Annu Rev Genet. 2002;36:721-50
references.pmid: 12359738
references.citation: Science. 2011 Oct 7;334(6052):86-9
references.pmid: 21980109
references.citation: Science. 2002 Dec 20;298(5602):2381-5
references.pmid: 12493913
references.citation: Nature. 2010 Oct 14;467(7317):832-8
references.pmid: 20881960
references.citation: BMC Genomics. 2014 Mar 28;15:246
references.pmid: 24678841
references.citation: PLoS Genet. 2013 Mar;9(3):e1003372
references.pmid: 23555287
references.citation: Nat Genet. 2006 Nov;38(11):1251-60
references.pmid: 17057719
references.citation: Genome Res. 2013 Jul;23(7):1089-96
references.pmid: 23539138
references.citation: BMC Med Genomics. 2008 Jun 04;1:22
references.pmid: 18533027
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Aug 29;360(1460):1605-7
references.pmid: 16096110
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Genetics. 2003 Jul;164(3):1205-19
references.pmid: 12871925
references.citation: Ann Eugen. 1951 Mar;15(4):323-54
references.pmid: 24540312
references.citation: Nat Genet. 2012 Feb 19;44(3):247-50
references.pmid: 22344220
references.citation: J Theor Biol. 1982 May 7;96(1):9-20
references.pmid: 7109659
references.citation: J Hum Evol. 2000 Jul;39(1):57-106
references.pmid: 10896812
references.citation: Genetics. 1975 Jun;80(2):395
references.pmid: 1132690
references.citation: Genetics. 2012 Oct;192(2):609-17
references.pmid: 22798486
references.citation: Mol Biol Evol. 2007 Mar;24(3):710-22
references.pmid: 17182896
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666
references.citation: Nat Genet. 2010 Jul;42(7):565-9
references.pmid: 20562875
references.citation: Heredity (Edinb). 2012 Apr;108(4):375-85
references.pmid: 21915150
references.citation: Evolution. 2013 Nov;67(11):3258-73
references.pmid: 24102455
references.citation: PLoS Genet. 2013 May;9(5):e1003520
references.pmid: 23737753
references.citation: Nat Genet. 2011 Aug 28;43(10):984-9
references.pmid: 21874001
references.citation: Genetics. 1973 May;74(1):175-95
references.pmid: 4711903
references.citation: Genetics. 1993 Oct;135(2):367-74
references.pmid: 8244001
references.citation: Cell. 2007 Dec 14;131(6):1179-89
references.pmid: 18083106
references.citation: Genetics. 1975 Dec;81(4):775-85
references.pmid: 1213275