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Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes
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Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes
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Journal Article
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Diabetes
/ Diabetes mellitus (non-insulin dependent)
/ Diabetes Mellitus, Type 2 - genetics
/ Exome
/ Female
/ Genetic Predisposition to Disease
/ Genetics
/ Genome-Wide Association Study
/ Glucose
/ Hepatocyte Nuclear Factor 1-alpha - genetics
/ Homeodomain Proteins - genetics
/ Humanities and Social Sciences
/ Humans
/ Insulin
/ Male
/ Polymorphism, Single Nucleotide
/ Science
