Abstract
Despite intensive study, most of the specific genetic factors that contribute to variation in human height remain undiscovered. We conducted a family-based linkage study of height in a unique cohort of very large nuclear families from a founder (Jewish) population. This design allowed for increased power to detect linkage, compared to previous family-based studies. Loci we identified in discovery families could explain an estimated lower bound of 6% of the variance in height in validation families. We showed that these loci are not tagging known common variants associated with height. Rather, we suggest that the observed signals arise from variants with large effects that are rare globally but elevated in frequency in the Jewish population.
Highlights
Height is a classic genetically complex quantitative trait with high heritability (~80%-90% [1,2])
We designed a unique study of height, in which we sought to increase the effective frequency of rare variants in our sample
Any variant segregating in our cohort has a minimum expected minor allele frequency (MAF) of ~1% if it is present in only one family, and higher if it is present in multiple families, regardless of its frequency in the general population
Summary
Height is a classic genetically complex quantitative trait with high heritability (~80%-90% [1,2]). The individual effect sizes of these variants are small, and all variants identified to date jointly explain only ~20% of the heritability of height. One proposed explanation for the gap between the overall heritability of height and that explained by common variants is the contribution of rare genetic variants with large phenotypic effects [5]. Several examples of large-effect variants that are rare globally but are more common in certain founder populations have been reported for height (in Sardinians [8] and in Puerto Ricans [9]) and diabetes (in Greenlanders [10]), identifying associations between rare variants and traits of interest typically requires very large sample sizes [11]. 750,000 participants were required to identify 32 rare variants (those with frequency
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