Long-range Haplotype Mapping in Hispanic/Latinos Reveals Loci for Short Stature. G. Belbin1,5,6, D. Ruderfer2,4,3, K. Slivinski5, MC. Yee8, J. Jeff5, O. Gottesman5, EA. Stahl2,3,5,6, RJF. Loos5,7, EP. Bottinger5, EE. Kenny1,4,5,6 1) Department of Genetics and Genomics, Icahn School of Medicine at Mt Sinai, New York, NY; 2) Broad Institute, Cambridge, MA; 3) Division of Psychiatric Genomics, Icahn School of Medicine at Mt Sinai, New York, NY; 4) Center for Statistical Genetics, Icahn School of Medicine at Mt Sinai, New York, NY; 5) The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mt Sinai, New York, NY; 6) Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mt Sinai, New York, NY; 7) The Mindich Child Health and Development Institute, Icahn School of Medicine at Mt Sinai, New York, NY; 8) Carnegie Institution for Science, Dept. of Plant Biology, Stanford, CA.
The Hispanic/Latino (HL) population of Northern Manhattan represents a diverse recent diaspora population, with 95% of the individuals reporting having grandparents born outside of the United States. Of these 43% report grandparents born in Puerto Rico, 23% the Dominican Republic, 13% Central America, and 5%, 4%, and 2% from Mexico, South America, and Europe respectively. Despite complex patterns of migration, admixture, and diversity, strong signatures of cryptic relatedness persist amongst HLs. We have detected long-range genomic tract sharing (>3cM), or identity-by-descent (IBD), across 5,194 HL in the Mount Sinai BioMe Biobank. We observed an average population level IBD sharing of 0.0025 in HL, which is 2.5- and 5-fold higher than that observed in BioMe European- and African-American populations, respectively. We hypothesize that these patterns of recent migration and genetic drift may drive some otherwise rare functional alleles to detectable frequency. We clustered groups of homologous IBD tracts (n=112,250) segregating in this HL population. We observed that IBD clusters represent a class of low frequency alleles (median minor allele frequency =0.0077, s.d.=0.0015). We performed a genome-wide association of the IBD clusters, or population-based linkage, to detect loci implicated in height, a highly heritable polygenic trait. 15 independent loci surpassed our empirically derived genome-wide significance threshold of <4.4710-4, 11 of which replicated in an independent cohort of BioMe HLs. Strikingly, two regions confer strong recessive effects. In the case of the top hit on 9q32 (MAF< 0.005; p<8x10-6), homozygous non-referent individuals were shorter by 6 or 10, for men or women, respectively, compared to the population mean (5 7 and 5 2 for men and women, respectively). In addition, IBD haplotypes in the 9q32 cluster harbored a significant enrichment of Native American ancestry (p<1x10-16). Finally, this interval contains a number of biologically compelling candidate genes, including COL27A1 and PALM2. This study demonstrates that rich population structure, rather than being a confounding factor in biomedical discovery efforts, may be leveraged to reveal novel genetic associations with complex human traits.
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