Structured mating: Patterns and implications

Abstract

Genetic similarity of spouses can reflect factors influencing mate choice, such as physical/behavioral characteristics, and patterns of social endogamy. Spouse correlations for both genetic ancestry and measured traits may impact genotype distributions (Hardy Weinberg and linkage equilibrium), and therefore genetic association studies. Here we evaluate white spouse-pairs from the Framingham Heart Study (FHS) original and offspring cohorts (N = 124 and 755, respectively) to explore spousal genetic similarity and its consequences. Two principal components (PCs) of the genome-wide association (GWA) data were identified, with the first (PC1) delineating clines of Northern/Western to Southern European ancestry and the second (PC2) delineating clines of Ashkenazi Jewish ancestry. In the original (older) cohort, there was a striking positive correlation between the spouses in PC1 (r = 0.73, P = 3x10(-22)) and also for PC2 (r = 0.80, P = 7x10(-29)). In the offspring cohort, the spouse correlations were lower but still highly significant for PC1 (r = 0.38, P = 7x10(-28)) and for PC2 (r = 0.45, P = 2x10(-39)). We observed significant Hardy-Weinberg disequilibrium for single nucleotide polymorphisms (SNPs) loading heavily on PC1 and PC2 across 3 generations, and also significant linkage disequilibrium between unlinked SNPs; both decreased with time, consistent with reduced ancestral endogamy over generations and congruent with theoretical calculations. Ignoring ancestry, estimates of spouse kinship have a mean significantly greater than 0, and more so in the earlier generations. Adjusting kinship estimates for genetic ancestry through the use of PCs led to a mean spouse kinship not different from 0, demonstrating that spouse genetic similarity could be fully attributed to ancestral assortative mating. These findings also have significance for studies of heritability that are based on distantly related individuals (kinship less than 0.05), as we also demonstrate the poor correlation of kinship estimates in that range when ancestry is or is not taken into account.

Fig 1. Flow diagram illustrating selection of FHS cohort participants for each analysis.

Black box—Participants used to detect global genetic ancestry and identify admixed and non-white individuals. Blue box—Participants used to characterize European/West Asian ancestry. Red box—Participants used for regression analysis using F and D. Green box—Participants used to calculate spousal genetic and phenotypic correlations and used in GCTA and PC-Relate calculations.

Fig 2. Flow diagram illustrating SNP selection for each analysis.

Black box—SNPs used to characterize global genetic ancestry and identify continentally admixed and non-white individuals; SNPs used in GCTA analysis; SNPs used for regression analysis using F; SNPs used to calculate spousal genetic correlations. Blue box—SNPs used to characterize European/West Asian ancestry. Red box—SNPs used for regression analysis using D.

Fig 3. Principal components analyses on FHS participants.

Principal components analysis on FHS participants with: Top left: Fig 3a, FHS and HGDP participants projected. Top right: Fig 3b, original cohort participants projected. Bottom left: Fig 3c, offspring cohort participants projected. Bottom right: Fig 3d, third generation cohort participants projected.

Fig 4. Scatter plots of spouses for PC1 and PC2, by generational cohort.

Scatter plots of spouse-pair male versus female: Top left: Fig 4a, PC1 in the original cohort. Top right: Fig 4b, PC2 in the original cohort. Bottom left: Fig 4c, PC1 in the offspring cohort. Bottom right: Fig 4d, PC2 in the offspring cohort.

Fig 5. Comparison of kinship estimates without ancestry adjustment (using GCTA) versus with ancestry adjustment (using PC-Relate).

(a) Original cohort. Blue color represents Ashkenazi spouse pairs; red color represents Northwestern European spouse pairs; green color represents Southern European spouse pairs; black color represents spouse pairs of different ancestry. (b) Offspring cohort. Blue color represents Ashkenazi spouse pairs; red color represents Northwestern European spouse pairs; green color represents Southern European spouse pairs; black color represents spouse pairs of different ancestry.

Fig 6. Probability density functions of spouse kinship estimates comparing results from GCTA (unadjusted for genetic ancestry) to those from PC-Relate (adjusted for genetic ancestry) in the FHS original cohort and offspring cohort.