“Fine-mapping, heritability estimation and rare-variant discovery in whole genome sequence studies”
Abstract: Risk of developing type 2 diabetes (T2D) is heritable, with over 403 independent genetic variants having been identified primarily through analysis of common variants in European ancestry populations. To further illuminate the genetic architecture of T2D, we conducted a whole-genome sequence (WGS) association study (>38x depth) of common, low-frequency, and rare variants in 9,663 individuals with T2D and 35,050 controls of diverse ancestry from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) study. Our analysis integrated regulatory annotations from pancreatic beta cells (gene expression, chromatin state, enhancers, and transcription factor binding sites). In a secondary analysis, we added to the case group individuals with T2D or near the biochemical diagnostic threshold for T2D, defined as fasting glucose>=6.1mmol/L or HbA1c>=6.0% when available. We conducted single variant analyses, assessed the SNP-based heritability of variants partitioned by our tissue-specific regulatory annotation and used this annotation to define ‘variant sets’ for SKAT and burden tests of rare-variants. Our results show that large-scale WGS analysis, with inclusion of ancestrally diverse samples, variant typing without imputation, use of tissue-specific regulatory annotation, and secondary analysis including sub-diagnostic threshold individuals identified new T2D risk loci and more fully revealed the genetic basis of T2D.
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