The First Genome-Wide Association Study (GWAS) for Type 2 Diabetes in Youth from the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multi-ethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth type 2 diabetes cases (mean age 15.1±2.9 y) and 6,061 diabetes-free adult controls (mean age 54.2±12.4 y). After stratifying by principal component-clustered ethnicity, we performed association analyses on ~10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified 7 genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P=3.2´10-8, odds ratio [OR]=1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P=8.0´10-20, OR 1.58), rs72982988 near MC4R (P=4.4´10-14, OR=1.53), rs200893788 in CDC123 (P=1.1´10-12, OR= 1.32), rs2237892 in KCNQ1 (P=4.8´10-11, OR=1.59), rs937589119 in IGF2BP2 (P=3.1´10-9, OR=1.34) and rs113748381 in SLC16A11 (P=4.1´10-8, OR=1.04). Secondary analysis with 856 diabetes-free youth controls uncovered an additional locus in CPEB2 (P=3.2´10-8, OR=2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome wide association study (GWAS) of youth-onset type 2 diabetes.

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The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium

10.2337/figshare.13607852 ◽

2021 ◽

Author(s):

Shylaja Srinivasan ◽

Ling Chen ◽

Jennifer Todd ◽

Jasmin Divers ◽

Samuel Gidding ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Linear Mixed Model ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Relationship Matrix ◽

Onset Type ◽

Genome Wide ◽

Diabetes In Youth

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multi-ethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth type 2 diabetes cases (mean age 15.1±2.9 y) and 6,061 diabetes-free adult controls (mean age 54.2±12.4 y). After stratifying by principal component-clustered ethnicity, we performed association analyses on ~10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified 7 genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P=3.2´10-8, odds ratio [OR]=1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P=8.0´10-20, OR 1.58), rs72982988 near MC4R (P=4.4´10-14, OR=1.53), rs200893788 in CDC123 (P=1.1´10-12, OR= 1.32), rs2237892 in KCNQ1 (P=4.8´10-11, OR=1.59), rs937589119 in IGF2BP2 (P=3.1´10-9, OR=1.34) and rs113748381 in SLC16A11 (P=4.1´10-8, OR=1.04). Secondary analysis with 856 diabetes-free youth controls uncovered an additional locus in CPEB2 (P=3.2´10-8, OR=2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome wide association study (GWAS) of youth-onset type 2 diabetes.

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Faculty Opinions recommendation of An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727678777.793535699 ◽

2017 ◽

Author(s):

Carlos Aguilar-Salinas

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

10.1101/2021.03.23.436581 ◽

2021 ◽

Author(s):

Samantha Streicher ◽

Unhee Lim ◽

S. Lani Park ◽

Yuqing Li ◽

Xin Sheng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

American Population ◽

Pancreatic Fat ◽

Genome Wide ◽

Multiethnic Cohort

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10 -8 ) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10 -8 ) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUT , and rs79967607 is in intron 1 of EPM2A . PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1 , that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

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