The integration of genomic data into health systems offers opportunities to identify genomic factors underlying the continuum of rare and common disease. We applied a population-scale haplotype association approach based on identity-by-descent (IBD) 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 strategies for understanding the continuum of genomic risk for common diseases, particularly in populations underrepresented in genomic medicine.

将基因组数据整合到卫生系统中提供了识别罕见和常见疾病连续体背后的基因组因素的机会。我们在大型多种族生物库中应用了基于血统同一性 (IBD) 的群体规模单倍型关联方法，将其应用于源自电子健康记录 (EHR) 的一系列疾病结果，并发现了肝病的风险位点。我们使用基因组测序和计算机方法将信号精细映射到基因ABCB4中的非编码变体 (c.2784−12T>C) 。体外分析证实了 ABCB4 前体 mRNA 的剪接变异被破坏。五分之四的纯合子有晚期肝病的证据，并且杂合子中与肝病存在显着相关性，表明该变异以等位基因剂量依赖性方式与肝病风险增加相关。人群水平筛查显示，波多黎各人中该变异的携带率为 1.95%，这可能是波多黎各创始人效应的结果。这项工作表明，在人口规模上整合 EHR 和基因组数据可以促进了解常见疾病的基因组风险连续性的策略，特别是在基因组医学中代表性不足的人群中。