The Myth of Random Mating: Evidence of ancestry-related assortative mating across 3 generations in Framingham, MA. R. Sebro1,2, G. Peloso3,4, J. Dupuis5,6, N. Risch1,7,8 1) Institute for Human Genetics, University of California, San Francisco, San Francisco, CA; 2) Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA; 3) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 4) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; 5) Department of Biostatistics, Boston University School of Public Health, Boston MA; 6) The National Heart, Lung and Blood Institutes Framingham Heart Study, Framingham, MA; 7) Department of Biostatistics and Epidemiology, University of California, San Francisco, San Francisco, CA; 8) Division of Research, Kaiser Permanente, Oakland, CA.

   The factors that influence spouse selection are important to geneticists because the mating pattern determines the genetic structure of a population. There has been evidence of positive assortative mating (PAM) related to several phenotypic traits like height. Ancestrally-related PAM is necessary for genetic population stratification, which means spouses are more likely to share genes of common ancestry. Prior studies have shown strong ancestry-related assortative mating among Latino populations. Here, Caucasian spouse pairs from the Framingham Heart Study (FHS) Original and Offspring cohorts (N=885) genotyped on Affymetrix 500K were analyzed using principal components (PC) analysis. Data from individuals genotyped in HapMap and the Human Genome Diversity Project (HGDP) were projected onto these PCs to facilitate interpretation. Based on these and other data, the first principal component delineates the prominent northwest-to-southeast European cline. In our data, there was clear clustering on this axis, probably separating individuals of English/Irish/German ancestry from those of Italian ancestry. The second principal component also reveals strong clustering, and likely reveals individuals of Ashkenazi Jewish ancestry. In the Original (older) cohort, there is a very strong correlation in PC1 between the spouses (r=0.73, P=2e-22) and also for PC2 (r=0.80, P=4e-29). In the Offspring cohort the spouse correlations were lower but still highly significant: r=0.38, P=3e-28 for PC1 and r=0.45, P =9e-40) for PC2. Examination of scatter plots for spouse pairs in the two generations reveals both a reduction in clustering and lower but still evident correlation in the Offspring cohort. Of genetic impact, we observed highly significant Hardy-Weinberg disequilibrium (homozygote excess) for SNPs loading heavily on PC1 and PC2 across 3 generations, and also highly significant linkage disequilibrium between the same set of SNPs located on different chromosomes. These results are consistent with demographic patterns of social homogamy which have existed in Framingham over several generations, and a general trend of reduced homogamy over time. While Framingham is not representative of the general US population, its historic mating patterns serve as a reminder that assumptions of Hardy Weinberg and Linkage Equilibrium need to be made with caution when applied to genetic loci that are related to ancestry in any population.

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