South Asian Patient Population Genetics Reveal Strong Founder Effects and High Rates of Homozygosity – New Resources for Precision Medicine

Abstract

Population-scale genetic studies can identify drug targets and allow disease risk to be predicted with resulting benefit for management of individual health risks and system-wide allocation of health care delivery resources. Although population-scale projects are underway in many parts of the world, genetic variation between population groups means that additional projects are warranted. South Asia has a population whose genetics is the least characterized of any of the world’s major populations. Here we describe GenomeAsia studies that characterize population structure in South Asia and that create tools for economical and accurate genotyping at population-scale. Prior work on population structure characterized isolated population groups, the relevance of which to large-scale studies of disease genetics is unclear. For our studies we used whole genome sequence information from 4,807 individuals recruited in the health care delivery systems of Pakistan, India and Bangladesh to ensure relevance to population-scale studies of disease genetics. We combined this with WGS data from 927 individuals from isolated South Asian population groups, and developed a custom SNP array (called SARGAM) that is optimized for future human genetic studies in South Asia. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of homozygosity that approach 100 times that seen in outbred populations. We describe founder effects that increase the power to associate functional variants with disease processes and that make South Asia a uniquely powerful place for population-scale genetic studies.

Quantifying and Understanding the Higher Risk of Atherosclerotic Cardiovascular Disease Among South Asian Individuals

“…62 We and others have recently started to assess the relationship of a polygenic predictor of ASCVD in South Asian individuals and to establish larger reference populations that may identify common or rare genetic factors distinct to South Asian individuals. [63][64][65][66] These results should be interpreted within the context of potential limitations. First, participant volunteers were recruited at sites across the United Kingdom at 40 to 69 years of age, raising the possibility of selection bias that limits generalizability to younger patients or individuals in other countries.…”

Long runs of homozygosity are correlated with marriage preferences across global population samples

“…For example, many marriages might occur between “cousins” who are actually quite distantly related. Alternatively, in many regions of the world, cousin marriage co-occurs with endogamy (marriage within defined sub-groups such as castes) [8]. Since endogamy can itself lead to excess recessive disease burden [9], the marginal effects of consanguinity might be small.…”