Abstract
Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 379,066 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1, which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1, a gene not previously implicated by human genetics in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10–12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10–14) as well as T2D diagnosis (OR = 4.15, p = 6.14 × 10–11). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.
Highlights
Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease
Using a p-value threshold adjusted for the number of variant sets and phenotypes tested (p ≤ 7.82 × 10–7), four variant sets in three genes significantly associated with glucose levels: GCK predicted loss of function (pLOF) (p = 1.56 × 10–9, 1.24 mmol/L increase), GCK damaging missense (p = 6.15 × 10–11, 0.61 mmol/L increase), GIGYF1 pLOF (p = 4.42 × 10–12, 0.77 mmol/L increase) and G6PC2 damaging missense variants (p = 4.62 × 10–83, 0.33 mmol/L decrease) (Fig. 1, Table 1)
The same variant sets associated with HbA1c levels along with 27 additional sets including HNF1A pLOF (p = 2.14 × 1 0–7, 4.01 mmol/mol increase), TNRC6B pLOF (p = 2.36 × 1 0–7, 3.94 mmol/mol increase) and PDX1 damaging missense variants (p = 2.54 × 1 0–7, 0.41 mmol/mol increase) (Fig. 1, Table 1 and Supplementary Table 2)
Summary
Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 379,066 exome-sequenced participants in the UK Biobank. Type 2 diabetes (T2D) is a disease that has been extensively studied in traditional array-based GWAS with hundreds of associations identified to d ate[9,10,11,12] These studies have given insight into some of the biological mechanisms contributing to T2D, most of the reported associations are with variants in non-coding regions, making identification of the causal gene challenging. Using whole exome sequences from the UK Biobank (UKBB) we performed gene-level collapsing tests to examine the association of pLOF and damaging missense variants in ~ 17,000 genes with biomarkers of glycemic control, glucose, and glycated hemoglobin (HbA1c), as well as T2D diagnosis
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