Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study

Theresa Wimberley; Isabell Brikell; Aske Astrup; Janne T Larsen; Liselotte V Petersen; Clara Albiñana; Bjarni J Vilhjálmsson; Cynthia M Bulik; Zheng Chang; Giuseppe Fanelli; Janita Bralten; Nina R Mota; Jordi Salas-Salvadó; Fernando Fernandez-Aranda; Monica Bulló; Barbara Franke; Anders Børglum; Preben B Mortensen; Henriette T Horsdal; Søren Dalsgaard

doi:10.1017/S0033291724001053

Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study

Psychol Med. 2024 May 27:1-10. doi: 10.1017/S0033291724001053. Online ahead of print.

Authors

Theresa Wimberley^{1

2

3}, Isabell Brikell^{1

4

5

6}, Aske Astrup¹, Janne T Larsen^{1

2}, Liselotte V Petersen^{1

2}, Clara Albiñana¹, Bjarni J Vilhjálmsson^{1

7}, Cynthia M Bulik^{5

8

9}, Zheng Chang⁵, Giuseppe Fanelli^{10

11

12}, Janita Bralten^{10

11}, Nina R Mota^{10

11}, Jordi Salas-Salvadó^{13

14

15}, Fernando Fernandez-Aranda^{15

16

17

18}, Monica Bulló^{13

14

15

19}, Barbara Franke^{10

11

20}, Anders Børglum^{2

6}, Preben B Mortensen^{1

2

3}, Henriette T Horsdal¹, Søren Dalsgaard^{1

2

21

22}

Affiliations

¹ The National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark.
² The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
³ Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark.
⁴ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
⁸ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.
⁹ Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, USA.
¹⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
¹² Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
¹³ Department of Biochemistry & Biotechnology, School of Medicine, IISPV, Rovira i Virgili University. Reus, Spain.
¹⁴ Institute of Health Pere Virgili (IISPV), Reus, Spain.
¹⁵ Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III (ISCIII). Madrid, Spain.
¹⁶ Clinical Psychology Unit, University Hospital Bellvitge, Hospitalet del Llobregat, Spain.
¹⁷ Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Hospitalet del Llobregat, Spain.
¹⁸ Psychoneurobiology of Eating and Addictive Behaviours Group, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet del Llobregat, Spain.
¹⁹ Center of Environmental, Food and Toxicological Technology - TecnATox, Rovira i Virgili University, 43201 Reus, Spain.
²⁰ Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
²¹ Child and Adolescent Psychiatry Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
²² Department of Clinical Medicine, Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 38801094
DOI: 10.1017/S0033291724001053

Abstract

Background: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM.

Methods: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders.

Results: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa.

Conclusions: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

Keywords: familial co-aggregation; genetic overlap; insulin resistance; non-insulin-dependent diabetes mellitus; polygenic risk.