Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes
Authors: Deaton Aimee M. , Parker Margaret M. , Ward Lucas D. , Flynn-Carroll Alexander O. , BonDurant Lucas , Hinkle Gregory , Akbari Parsa , Lotta Luca A. ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Abecasis Goncalo , Baras Aris , Cantor Michael , Coppola Giovanni , Economides Aris , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Shuldiner Alan , Karalis Katia , Deubler Andrew , Siminovitch Katherine ,   Sequencing and Lab Operations, Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Overton John D. , Schleicher Thomas D. , Padilla Maria Sotiropoulos , Widom Louis , Wolf Sarah E. , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H. ,   Genome Informatics, Bai Xiaodong , Balasubramanian Suganthi , Blumenfeld Andrew , Boutkov Boris , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Maxwell Evan K. , Nafde Mona , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Reid Jeffrey G. , Salerno William , Staples Jeffrey C. ,   Clinical Informatics, Cantor Michael , Li Dadong ,   Translational and Analytical Genetics, Locke Adam , Verweij Niek , Nielsen Jonas , Bovijn Jonas , De Tanima , Haas Mary , Akbari Parsa , Sosina Olukayode ,   Research Program Management, Jones Marcus B. , Mighty Jason , LeBlanc Michelle G. , Mitnaul Lyndon J. ,   DiscovEHR Collaboration,   Regeneron Personnel, Abecasis Goncalo , Baras Aris , Cantor Michael , Coppola Giovanni , Economides Aris , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Shuldiner Alan , Deubler Andrew , Karalis Katia , Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Schleicher Thomas D. , Padilla Maria Sotiropoulos , Toledo Karina , Widom Louis , Wolf Sarah E. , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H. , Bai Xiaodong , Balasubramanian Suganthi , Barnard Leland , Blumenfeld Andrew , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Maxwell Evan K. , Salerno William , Staples Jeffrey C. , Yadav Ashish , Li Dadong , Jones Marcus B. , Mitnaul Lyndon J. , Mighty Jason , Deubler Andrew , Karalis Katia , Siminovitch Katherine ,   Geisinger Personnel, Adams Lance J. , Blank Jackie , Bodian Dale , Boris Derek , Buchanan Adam , Carey David J. , Colonie Ryan D. , Davis F. Daniel , Hartzel Dustin N. , Kelly Melissa , Kirchner H. Lester , Leader Joseph B. , Ledbetter David H. , Manus J. Neil , Martin Christa L. , Metpally Raghu P. , Meyer Michelle , Mirshahi Tooraj , Oetjens Matthew , Person Thomas Nate , Still Christopher , Strande Natasha , Sturm Amy , Wagner Jen , Williams Marc , Baras Aris , Nioi Paul 
Published: November 2021

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.