Large-scale identity-by-descent mapping discovers rare haplotypes of large effect. Suyash Shringarpure 23andMe, Inc. ASHG 2017

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1 Large-scale identity-by-descent mapping discovers rare haplotypes of large effect Suyash Shringarpure 23andMe, Inc. ASHG

2 Why care about rare variants of large effect? Months from randomization 2

3 The 23andMe cohort is well-powered for rare variant associations 2M+ customers ~85% 700M+ consent to research survey questions answered 3

4 Rare variants of large effect are likely to be recent 4 (Lupski et al., 2011, Cell)

5 Recent variants identical-by-descent haplotypes A B C D E A B C D E IBD pairs (A.B), (B,C), (A,C), (E,) 5

6 IBD clusters as rare variant proxies IBD cluster : Group of samples with all / most pairs IBD with each other in a genomic region IBD clusters represent shared haplotypes, and therefore shared rare variants IBD mapping : inding IBD clusters enriched for cases 6

7 Outline IBD mapping method Experiments Next steps and conclusions 7

8 Step 1 : Infer IBD segments genomewide with IBD64 10 Mb 25 Mb A B C IBD64 D A,B B,C A,C E, E 8 (Henn et al., 2012, PLoS One)

9 Step 2 : Construct and cluster IBD graphs in windows A,B B,C A,C E, B A B A E C D A A D B D A E C D E C E C B E C B D MCL : Markov clustering ( org/mcl/man/m cl.html) 9

10 Step 3 : Choose candidate clusters to test B A E C D 2 cases, 4 controls PC1 = Binomial test (2 cases in a cluster of 3) PC2 = Binomial test (0 case in a cluster of 2) A B C D E PC3 = Binomial test (0 cases in a cluster of 1) 10

11 Step 4 : Logistic test with clusters and covariates Phenotype Cluster member? Age Sex M M 2 cases, 4 controls Logistic M 11

12 IBD mapping experiments Phenotype Population Sample size Number of IBD segments (millions) Breast or ovarian cancer European 114, Parkinson s disease Ashkenazi 43,173 1,

13 A rare haplotype of large effect in BRCA2 Phenotype: Breast or ovarian cancer Chromosome 13 Cluster = 31 cases, 29 controls Rest = cases, controls Cluster frequency = 0.05 % Odds ratio = P-value = 1.3e-12 13

14 A rare haplotype of large effect in LRRK2 Phenotype : Parkinson s disease Chromosome 12 Cluster = 125 cases, 547 controls Rest = 987 cases, controls Cluster frequency = 1.5 % Odds ratio = 9.42 P-value = 3.5e-68 14

15 Associated clusters tag rare protein-coding variants Phenotype Population Sample size Cluster size SNP (Gene) Population alt allele frequency (%) Cluster alt allele frequency (%) Breast or ovarian cancer European 114, rs / Ser1982Argfs (BRCA2) Parkinson s disease Ashkenazi 43, rs / G2019S (LRRK2)

16 Novel IBD mapping hit in JAG1 for prostate cancer Chromosome 20 Cluster = 14 cases, 40 controls Rest = cases, controls Cluster frequency = 0.049% Odds ratio = 8.22 P-value = 1.5e-7 16

17 JAG1 cluster overlaps a wide genomic region 17

18 JAG1 is associated with prostate cancer in literature 18

19 Next steps Test all clusters Generate phased IBD at scale Validate more hits by sequencing 19

20 Conclusions IBD mapping can tag rare variation that can be hard to impute and may only be accessible through sequencing. We show results of IBD mapping on the 23andMe cohort. IBD clusters can prioritize samples for sequencing. More improvements to be made in IBD inference and downstream association. 20

21 Acknowledgements 23andMe research participants David Hinds Vladimir Vacic Steve Pitts Robert Gentleman Adam Auton 23andMe Research Team 21