Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

Dina Mansour Aly; Om Prakash Dwivedi; Rashmi B Prasad; Annemari Käräjämäki; Rebecka Hjort; Manonanthini Thangam; Mikael Åkerlund; Anubha Mahajan; Miriam S Udler; Jose C Florez; Mark I McCarthy; Regeneron Genetics Center; Julia Brosnan; Olle Melander; Sofia Carlsson; Ola Hansson; Tiinamaija Tuomi; Leif Groop; Emma Ahlqvist

doi:10.1038/s41588-021-00948-2

Genome-wide association analyses highlight etiological differences underlying newly defined subtypes of diabetes

Nat Genet. 2021 Nov;53(11):1534-1542. doi: 10.1038/s41588-021-00948-2. Epub 2021 Nov 4.

Authors

Dina Mansour Aly¹, Om Prakash Dwivedi², Rashmi B Prasad¹, Annemari Käräjämäki^{3

4}, Rebecka Hjort⁵, Manonanthini Thangam¹, Mikael Åkerlund¹, Anubha Mahajan^{6

7}, Miriam S Udler^{8

9

10}, Jose C Florez^{8

9

10}, Mark I McCarthy^{11

12

13

7}; Regeneron Genetics Center; Julia Brosnan¹⁴, Olle Melander¹, Sofia Carlsson⁵, Ola Hansson^{1

2}, Tiinamaija Tuomi^{1

2

15

16}, Leif Groop^{1

2}, Emma Ahlqvist¹⁷

Collaborators

Affiliations

¹ Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
² Finnish Institute for Molecular Medicine, Helsinki University, Helsinki, Finland.
³ Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
⁴ Diabetes Center, Vaasa Health Care Center, Vaasa, Finland.
⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Genentech, South San Francisco, CA, USA.
⁸ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Boston, MA, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford, UK.
¹² Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹³ Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK.
¹⁴ Pfizer Inc., Cambridge, MA, USA.
¹⁵ Folkhälsan Research Center, Helsinki, Finland.
¹⁶ Abdominal Center, Endocrinology, Helsinki University Central Hospital, Research Program for Diabetes and Obesity, Center of Helsinki, Helsinki, Finland.
¹⁷ Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden. Emma.Ahlqvist@med.lu.se.

PMID: 34737425
DOI: 10.1038/s41588-021-00948-2

Abstract

Type 2 diabetes has been reproducibly clustered into five subtypes with different disease progression and risk of complications; however, etiological differences are unknown. We used genome-wide association and genetic risk score (GRS) analysis to compare the underlying genetic drivers. Individuals from the Swedish ANDIS (All New Diabetics In Scania) study were compared to individuals without diabetes; the Finnish DIREVA (Diabetes register in Vasa) and Botnia studies were used for replication. We show that subtypes differ with regard to family history of diabetes and association with GRS for diabetes-related traits. The severe insulin-resistant subtype was uniquely associated with GRS for fasting insulin but not with variants in the TCF7L2 locus or GRS reflecting insulin secretion. Further, an SNP (rs10824307) near LRMDA was uniquely associated with mild obesity-related diabetes. Therefore, we conclude that the subtypes have partially distinct genetic backgrounds indicating etiological differences.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Body Mass Index
Child
Child, Preschool
Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 2 / etiology*
Diabetes Mellitus, Type 2 / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Infant
Insulin Secretion / genetics
Lipids / blood
Lipids / genetics
Middle Aged
Polymorphism, Single Nucleotide
Sweden
Young Adult

Substances

Lipids