Gene-level analysis of rare variants in 363,977 whole exome sequences reveals an association of GIGYF1 loss of function with diabetes

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 T2D diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified known associations with diabetes including variants in GCK, HNF1A and PDX1, genes involved in Mendelian forms of diabetes. Novel associations were identified for GIGYF1 predicted loss of function (pLOF), TNRC6B pLOF and PFAS predicted damaging missense variants. Multiple rare variants contributed to these associations, including singleton variants. The most significant novel associations were seen for GIGYF1 pLOF which associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 x 10-12) and HbA1c (4.33 mmol/mol, p = 1.28 x 10-14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x 10-11). GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. An independent common variant association for glucose and T2D was identified at GIGYF1 which replicated in additional datasets. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.