Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes
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-sequen...
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Nature Portfolio
2021
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oai:doaj.org-article:3eba2ec7d59241e2a1ea8ba7d9c77d4a2021-11-08T10:56:06ZGene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes10.1038/s41598-021-99091-52045-2322https://doaj.org/article/3eba2ec7d59241e2a1ea8ba7d9c77d4a2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99091-5https://doaj.org/toc/2045-2322Abstract 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.Aimee M. DeatonMargaret M. ParkerLucas D. WardAlexander O. Flynn-CarrollLucas BonDurantGregory HinkleParsa AkbariLuca A. LottaRegeneron Genetics CenterDiscovEHR CollaborationAris BarasPaul NioiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) |
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Medicine R Science Q Aimee M. Deaton Margaret M. Parker Lucas D. Ward Alexander O. Flynn-Carroll Lucas BonDurant Gregory Hinkle Parsa Akbari Luca A. Lotta Regeneron Genetics Center DiscovEHR Collaboration Aris Baras Paul Nioi Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| description |
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. |
| format |
article |
| author |
Aimee M. Deaton Margaret M. Parker Lucas D. Ward Alexander O. Flynn-Carroll Lucas BonDurant Gregory Hinkle Parsa Akbari Luca A. Lotta Regeneron Genetics Center DiscovEHR Collaboration Aris Baras Paul Nioi |
| author_facet |
Aimee M. Deaton Margaret M. Parker Lucas D. Ward Alexander O. Flynn-Carroll Lucas BonDurant Gregory Hinkle Parsa Akbari Luca A. Lotta Regeneron Genetics Center DiscovEHR Collaboration Aris Baras Paul Nioi |
| author_sort |
Aimee M. Deaton |
| title |
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| title_short |
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| title_full |
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| title_fullStr |
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| title_full_unstemmed |
Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes |
| title_sort |
gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of gigyf1 loss of function with type 2 diabetes |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/3eba2ec7d59241e2a1ea8ba7d9c77d4a |
| work_keys_str_mv |
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