Beschreibung:
<jats:p>Our understanding of the genetic basis of T2D has been significantly advanced by identification of T2D loci through analysis of common variation; however, evidence suggests a role for rare regulatory variation influencing T2D. We leveraged the largest available whole genome sequence (WGS) data from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) initiative and diabetes-centric genomic function data to the interpretation of results. We performed single-variant pooled-ancestry association analyses with (&gt;30x deep sequence) WGS in 13,200 individuals (2,601 T2D and 10,599 controls) from 6 studies. The association analyses were performed in the Analysis Commons hosted on DNANexus. We demonstrated the utility of the OASIS (Omics Analysis, Search and Information System) platform and integrating diabetes-specific functional annotation in a recently discovered locus (GIP-IGF2BP1) to fine-map to the likely causal variants. Our results identified common (minor allele frequency [MAF] &gt; 0.05) variant associations (P &lt; 5 × 10-8) at a known locus with T2D: TCF7L2 (rs7903146, P = 3.8 × 10-12). We also identified a potentially novel association on Chr15q21 with 27 rare variants (MAF = 0.2%, P =1.3 × 10-8, r2=1) spanning a 7.5 MB region. In the Old Order Amish study, 53 individuals carry the haplotype tagged by these 27 variants; 17% of carriers are diagnosed with T2D compared to 3% of the non-carriers. Interrogation of the GIP-IGF2BP1 locus, utilizing diabetes-specific annotation and association evidence of both common and rare non-coding variants, within the OASIS browser implicated nearby genes in the region as being the likely biologic candidates.</jats:p>
<jats:p>In conclusion, preliminary results suggest WGS analysis can discover novel loci for complex traits. Work is ongoing to refine annotation for rare variant association tests and perform functional fine-mapping across the genome. We soon will extend our analysis into the next release of WGS data from TOPMed (N∼69,000 individuals).</jats:p>
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<jats:title>Disclosure</jats:title>
<jats:p>J. Wessel: Employee; Spouse/Partner; Eli Lilly and Company. J.A. Brody: None. A. Manning: None.</jats:p>
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