| 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 |
| Journal: | Scientific Reports |
| Published: | 3 Nov 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34732801/ |
| DOI: | https://doi.org/10.1038/s41598-021-99091-5 |
| URL: | https://www.nature.com/articles/s41598-021-99091-5.pdf |
| Citations: | 34 (19 in last 2 years) as of 8 Aug 2024 |
Publication 4880
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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.</p>
130 Authors
- Goncalo Abecasis
- Aris Baras
- Michael Cantor
- Giovanni Coppola
- Aris Economides
- Luca A. Lotta
- John D. Overton
- Jeffrey G. Reid
- Alan Shuldiner
- Katia Karalis
- Andrew Deubler
- Katherine Siminovitch
- Christina Beechert
- Caitlin Forsythe
- Erin D. Fuller
- Zhenhua Gu
- Michael Lattari
- Alexander Lopez
- John D. Overton
- Thomas D. Schleicher
- Maria Sotiropoulos Padilla
- Louis Widom
- Sarah E. Wolf
- Manasi Pradhan
- Kia Manoochehri
- Ricardo H. Ulloa
- Xiaodong Bai
- Suganthi Balasubramanian
- Andrew Blumenfeld
- Boris Boutkov
- Gisu Eom
- Lukas Habegger
- Alicia Hawes
- Shareef Khalid
- Olga Krasheninina
- Rouel Lanche
- Adam J. Mansfield
- Evan K. Maxwell
- Mona Nafde
- Sean O'Keeffe
- Max Orelus
- Razvan Panea
- Tommy Polanco
- Ayesha Rasool
- Jeffrey G. Reid
- William Salerno
- Jeffrey C. Staples
- Michael Cantor
- Dadong Li
- Adam Locke
- Niek Verweij
- Jonas Nielsen
- Jonas Bovijn
- Tanima De
- Mary Haas
- Parsa Akbari
- Olukayode Sosina
- Marcus B. Jones
- Jason Mighty
- Michelle G. LeBlanc
- Lyndon J. Mitnaul
- Goncalo Abecasis
- Aris Baras
- Michael Cantor
- Giovanni Coppola
- Aris Economides
- Luca A. Lotta
- John D. Overton
- Jeffrey G. Reid
- Alan Shuldiner
- Andrew Deubler
- Katia Karalis
- Christina Beechert
- Caitlin Forsythe
- Erin D. Fuller
- Zhenhua Gu
- Michael Lattari
- Alexander Lopez
- Thomas D. Schleicher
- Maria Sotiropoulos Padilla
- Karina Toledo
- Louis Widom
- Sarah E. Wolf
- Manasi Pradhan
- Kia Manoochehri
- Ricardo H. Ulloa
- Xiaodong Bai
- Suganthi Balasubramanian
- Leland Barnard
- Andrew Blumenfeld
- Gisu Eom
- Lukas Habegger
- Alicia Hawes
- Shareef Khalid
- Evan K. Maxwell
- William Salerno
- Jeffrey C. Staples
- Ashish Yadav
- Dadong Li
- Marcus B. Jones
- Lyndon J. Mitnaul
- Jason Mighty
- Andrew Deubler
- Katia Karalis
- Katherine Siminovitch
- Lance J. Adams
- Jackie Blank
- Dale Bodian
- Derek Boris
- Adam Buchanan
- David J. Carey
- Ryan D. Colonie
- F. Daniel Davis
- Dustin N. Hartzel
- Melissa Kelly
- H. Lester Kirchner
- Joseph B. Leader
- David H. Ledbetter
- J. Neil Manus
- Christa L. Martin
- Raghu P. Metpally
- Michelle Meyer
- Tooraj Mirshahi
- Matthew Oetjens
- Thomas Nate Person
- Christopher Still
- Natasha Strande
- Amy Sturm
- Jen Wagner
- Marc Williams
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