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Leveraging Health Systems Data to Characterize a Large Effect Variant Conferring Risk for Liver Disease in Puerto Ricans

By Gillian M Belbin, Stephanie Rutledge, Tetyana Dodatko, Sinead Cullina, Michael C. Turchin, Sumita Kohli, Denis Torre, Muh-ching Yee, Christopher R Gignoux, Noura S Abul-Husn, Sander Houten, Eimear E. Kenny

Posted 06 Apr 2021
medRxiv DOI: 10.1101/2021.03.31.21254662

Broad-scale adoption of genomic data in health systems offers opportunities for extending methods for the discovery of variation linked to underlying genomic disease risk. We applied a population-scale linkage mapping approach in a large multi-ethnic biobank to a spectrum of disease outcomes derived from Electronic Health Records (EHRs) and uncovered a risk locus for liver disease. We used genome sequencing and in silico approaches to fine-map the signal to a non-coding variant (c.2784-12T>C) in the gene ABCB4. In vitro analysis confirmed the variant disrupted splicing of the ABCB4 pre-mRNA. Four of five homozygotes had evidence of advanced liver disease, and there was a significant association with liver disease among heterozygotes, suggesting the variant is linked to increased risk of liver disease in an allele dose-dependent manner. Population-level screening revealed the variant to be at a carrier rate of 1.95% in Puerto Rican individuals, likely as the result of a Puerto Rican founder effect. This work demonstrates that integrating EHR and genomic data at a population-scale can facilitate novel strategies for understanding the continuum of genomic risk for common diseases, particularly in populations underrepresented in genomic medicine.

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