Population differentiation analysis of 54,734 European Americans reveals independent evolution of ADH1B gene in Europe and East Asia

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1 Population differentiation analysis of 54,734 European Americans reveals independent evolution of ADH1B gene in Europe and East Asia Kevin Galinsky Harvard T. H. Chan School of Public Health American Society of Human Genetics October 10, 2015

2 Population differentiation can detect recent selection Sabeti et al Science 2

3 Example: High-altitude EPAS1 gene in Tibetan populations Yi et al Science 3

4 Selected loci generate false-positive signals in GWAS Population Stratification Phenotype Natural Selection Population Differentiation Ancestry Informative Markers Price et al PLoS Genet, Tian et al PLoS Genet 4

5 Outline Overview of method Simulations Signals of selection in GERA data 5

6 Ancestral Population Population differentiation examines allele frequency differences Pop 1 p1 E p 1 p 2 = 0 Var p 1 p 2 = 2F ST p 1 p p 1 p 2 ~N 0,2F ST p 1 p F ST p 1 p 2 p Pop 2 p2 Weir & Hill 2002 Annu Rev Genet, Bhatia et al Genome Res 6

7 Ancestral Population Population differentiation examines allele frequency differences Pop 1 p1 Sample 1 p 1 p i~n p i, p i 1 p i 2N i p 1 p 2 ~N 0,2F ST p 1 p p Pop 2 p2 Sample 2 p 2 7

8 Ancestral Population Population differentiation examines allele frequency differences Pop 1 p1 Sample 1 p 1 D = p 1 p 2 D~N 0, p 1 p 2F ST + 1 2N N 2 p Smaller F ST = More Power Greater sample size = More Power Pop 2 p2 Bhatia et al AJHG Sample 2 p 2 8

9 Ancestral Population Extending selection statistic to fractional ancestry Pop 1 p1 p 1 and p 2 still follow normal distribution! p Sample Pop 2 p2 α: ancestry x: genotypes p 1 = at x 2a T 1 p 2 = 1 a T x 2 1 a T 1 D still follows a normal distribution! But variance unknown

10 Ancestral Population Approach extends to PCs in the absence of population information Pop 1 p1 Y: normalized genotypes y i = x i 2p i 2p i 1 p i p Sample X: genotypes Eigenvectors v 1,, v K Correspond to ancestry α k = β 0k + β 1k v k Pop 2 p2 D ik y i v k Galinsky et al. biorxiv (under revision, AJHG)

11 Normalizing the SNP loadings with eigenvalues Two problems: Var(D) unknown D = Cyv; C unkown PCA is SVD: Y UΣV T U and V orthonormal Σ diagonal U = YVΣ 1 Var U ij = M 1 M Σ k 2 y iv k 2 ~χ

12 Selection statistic produces genome-wide significant signals Method produces a p-value Correct for M SNPs tested K PCs examined 12

13 Outline Overview of Method Simulations Signals of selection in GERA data 13

14 Ancestral Population Simulation scheme Pop 1 p1 Sample 1 X1 F ST PCs p Pop 2 p2 Sample 2 X2 Differentiated SNPs: D = p 1 p 2 Z 1, Z 2 Selection 14

15 Selection statistic under null is well calibrated 15

Power Smaller F ST = More Power 1 0.8 0.6 0.4 0.2 D~N 0, p 1 p 2F ST + 1 2N 1 + 1 2N 2 F_ST 0.

16 Power Smaller F ST = More Power D~N 0, p 1 p 2F ST + 1 2N N 2 F_ST Population Differentiation ( D = p 1 -p 2 ) 16

Power Larger sample size = More Power 1 0.8 0.6 0.4 0.2 F ST = 0.

17 Power Larger sample size = More Power F ST = D~N 0, p 1 p 2F ST + 1 2N N 2 N 50k 20k 10k 5k 2k 1k Population Differentiation ( D = p 1 -p 2 ) 17

18 Outline Overview of Method Simulations Signals of selection in GERA data 18

19 Detecting natural selection in a real dataset Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort Looked at samples with European ancestry 670,176 SNPs 62,318 Samples Banda et al Genetics 19

20 Data processing steps Original 670k 62k QC Filtering QC Remove: 609k 55k Related samples <90% European Ancestry Missing data SNPs Low MAF SNPs Selection LD Filtering HWE filter LD filter 162k LD PCA PCs 55k FastPCA Linear time algorithm 57 minutes CPU time 2.6 GB RAM SNPs Samples 20

21 PC1 selection signals LCT, ADH1B, HLA, OCA2 LCT ADH1B HLA OCA2 21

22 PC2 selection signals IGFBP3, IGH, OCA2 IGFBP3 IGH OCA2 22

23 PC3 selection signals LCT, IRF4, HLA, OCA2 LCT IRF4 HLA OCA2 23

24 PC4 selection signals IRF4, HLA, Chromosome 8 inversion IRF4 HLA Chr8 Inversion Tian et al PLoS Genet 24

25 Removing significant regions removes LD signals LCT ADH1B HLA PC1 OCA2 IGFBP3 PC2 IGH OCA2 LCT IRF4 HLA PC3 OCA2 IRF4 PC4 No chromosome 8 inversion HLA Tian et al PLoS Genet 25

26 Detect regions with novel selection Locus Chr Region (Mb) Best Hit PC p-value LCT rs ADH1B rs IRF rs HLA rs IGFBP rs Chr8 Inversion rs IGH rs OCA rs Genome-wide significant after testing 609k SNPs 4 PCs = 2.4M hypotheses p-value threshold =

27 ADH1B: Known phenotype Under selection East Asia Alcohol dehydrogenase rs is C/T SNP and Arg47His ADH1B*47His variant more active Oxidizes ethanol to acetaldehyde Protective against alcoholism Known to be under selection in East Asia Detected novel signal of selection in Europeans Han et al AJHG, Dick et al Alcohol Clin Exp Res 27

28 ADH1B: Independent selection event in Europeans Selection in East Asia detected using EHH methods H7 haplotype detected Contains variant at regulatory SNP rs Variant not found in Europeans Haplotype rs rs Asian (CHB, CHS, JPT) European (CEU, FIN, GBR, IBS, TSI) African (ASW, LWK, YRI) H5 G T 0.36% 1.12% 0% H5b G T 0.18% 0.56% 0% H6 G T 12.1% 0.28% 0% H7 A T 60.9% 0% 0% Other G C 28.0% 91.7% 100% Han et al AJHG, Yi et al Ann Hum Genet 28

29 Novel selection signal at IGFBP3: Gene with cancer and BP phenotypes Insulin-like growth factor-binding protein 3 IGF transport protein in blood Mediates effects of IGF IGF associated with: Breast cancer Implicated in other cancers Blood pressure phenotypes Al-Zahrani et al. Hum. Mol. Genet. 2006, Jogie-Brahim et al. Endocr Rev. 2009, Ganesh et al. AJHG 2014, Zhu et al, AJHG

30 Novel selection signal IGH: Locus associated with MS Immunoglobulin heavy locus Contains variants for heavy chains of antibodies Associated with multiple sclerosis Thought to be an autoimmune disorder Buck et al. Ann. Neurol

31 Conclusions Presented method to detect natural selection Without a priori ancestry Genome-wide significant signals Novel selection in GERA ADH1B in Europeans IGFBP3 IGH 31

32 Acknowledgements Alkes Price Gaurav Bhatia Po-Ru Loh Galinsky et al. biorxiv (under revision, AJHG) Sayan Mukherjee Google Stoyan Georgiev Nick Patterson 32

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