Genetic disease risks of under-represented founder populations in New York City

Abstract The detection of founder pathogenic variants, those observed in high frequency only in a group of individuals with increased inter-relatedness, can help improve delivery of health care for that community. We identified 16 groups with shared ancestry, based on genomic segments that are shared through identity by descent (IBD), in New York City using the genomic data of 25,366 residents from the All Of Us Research Program and the Mount Sinai Bio Me biobank. From these groups we defined 8 as founder populations, mostly communities currently under-represented in medical genomics research, such as Puerto Rican, Garifuna and Filipino/Pacific Islanders. The enrichment analysis of ClinVar pathogenic or likely pathogenic (P/LP) variants in each group identified 202 of these damaging variants across the 8 founder populations. We confirmed disease-causing variants previously reported to occur at increased frequencies in Ashkenazi Jewish and Puerto Rican genetic ancestry groups, but most of the damaging variants identified have not been previously associated with any such founder populations, and most of these founder populations have not been described to have increased prevalence of the associated rare disease. Twenty-five of 51 variants meeting Tier 2 clinical screening criteria (1/100 carrier frequency within these founder groups) have never previously been reported. We show how population structure studies can provide insights into rare diseases disproportionately affecting under-represented founder populations, delivering a health care benefit but also a potential source of stigmatization of these communities, who should be part of the decision-making about implementation into health care delivery. Author Summary It is well recognized that genomic studies have been biased towards individuals of European ancestry, and that obtaining medical insights for populations under-represented in medical genomics is crucial to achieve health equity. Here, we use genomic information to identify networks of individuals in New York City who are distinctively related to each other, allowing us to define populations with common genetic ancestry based on genetic similarities rather than by self-reported race or ethnicity. In our study of >25,000 New Yorkers, we identified eight highly-interrelated founder populations, with 202 likely disease-causing variants with increased frequencies in specific founder populations. Many of these population-specific variants are new discoveries, despite their high frequency in founder populations. Studying recent genetic ancestry can help reveal population-specific disease insights that can help with early diagnosis, carrier screening, and opportunities for targeted therapies that all help to reduce health disparities in genomic medicine.