Familial aggregation and shared genetic loading for major psychiatric disorders and type 2 diabetes

Abstract

Aims/hypothesis

Psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BPD), are highly comorbid with type 2 diabetes. However, the mechanisms underlying such comorbidity are understudied. This study explored the familial aggregation of common psychiatric disorders and type 2 diabetes by testing family history association, and investigated the shared genetic loading between them by testing the polygenic risk score (PRS) association.

Methods

A total of 105,184 participants were recruited from the Taiwan Biobank, and genome-wide genotyping data were available for 95,238 participants. The Psychiatric Genomics Consortium-derived PRS for SCZ, MDD and BPD was calculated. Logistic regression was used to estimate the OR with CIs between a family history of SCZ/MDD/BPD and a family history of type 2 diabetes, and between the PRS and the risk of type 2 diabetes.

Results

A family history of type 2 diabetes was associated with a family history of SCZ (OR 1.23, 95% CI 1.08, 1.40), MDD (OR 1.19, 95% CI 1.13, 1.26) and BPD (OR 1.26, 95% CI 1.15, 1.39). Compared with paternal type 2 diabetes, maternal type 2 diabetes was associated with a higher risk of a family history of SCZ. SCZ PRS was negatively associated with type 2 diabetes in women (OR 0.92, 95% CI 0.88, 0.97), but not in men; the effect of SCZ PRS reduced after adjusting for BMI. MDD PRS was positively associated with type 2 diabetes (OR 1.04, 95% CI 1.00, 1.07); the effect of MDD PRS reduced after adjusting for BMI or smoking. BPD PRS was not associated with type 2 diabetes.

Conclusions/interpretation

The comorbidity of type 2 diabetes with psychiatric disorders may be explained by shared familial factors. The shared polygenic loading between MDD and type 2 diabetes implies not only pleiotropy but also a shared genetic aetiology for the mechanism behind the comorbidity. The negative correlation between polygenic loading for SCZ and type 2 diabetes implies the role of environmental factors.

Graphical abstract

 

 

 

Data availability

The data that support the findings of this study are available from the Taiwan Biobank. GWAS summary statistics for SCZ, MDD and BPD are available at the PGC website https://www.med.unc.edu/pgc/. GWAS summary statistics for Asian type 2 diabetes are available at https://blog.nus.edu.sg/agen/summary-statistics/t2d-2020/; those for European type 2 diabetes are available at http://diagram-consortium.org/downloads.html

Abbreviations

aOR:

Adjusted odds ratio

BPD:

Bipolar disorder

EAS:

East Asian population

EUR:

European population

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

MDD:

Major depressive disorder

PC:

Principal component

PGC:

Psychiatric Genomics Consortium

PRS:

Polygenic risk score

SCZ:

Schizophrenia

TWB:

Taiwan Biobank

Nutrigenomics Institute is not responsible for the comments and opinions included in this article

Published: 23 February 2022

• Mei-Hsin Su,
• Ying-Hsiu Shih,
• Yen-Feng Lin,
• Pei-Chun Chen,
• Chia-Yen Chen,
• Po-Chang Hsiao,
• Yi-Jiun Pan,
• Yu-Li Liu,
• Shih-Jen Tsai,
• Po-Hsiu Kuo,
• Chi-Shin Wu,
• Yen-Tsung Huang &
• Shi-Heng Wang

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Authors’ relationships and activities

CYC is an employee of Biogen. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

This work was supported by the Taiwanese National Health Research Institutes (NHRI-EX109-10931PI and NHRI-EX110-10931PI).

Author information

Affiliations

1. Department of Occupational Safety and Health, College of Public Health, China Medical University, Taichung, Taiwan

Mei-Hsin Su & Shi-Heng Wang

1. Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan

Ying-Hsiu Shih, Pei-Chun Chen & Shi-Heng Wang

1. Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan

Yen-Feng Lin & Yu-Li Liu

1. Biogen, Cambridge, MA, USA

Chia-Yen Chen

1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Chia-Yen Chen

1. College of Public Health, National Taiwan University, Taipei, Taiwan

Po-Chang Hsiao & Po-Hsiu Kuo

1. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan

Yi-Jiun Pan

1. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan

Shih-Jen Tsai

1. Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan

Chi-Shin Wu

1. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

Yen-Tsung Huang

Contributions

SHW conceptualised and designed the study. MHS and YHS drafted the manuscript and performed the data analysis. YFL, PCC, CYC, PCH, YJP, YLL, SJT, PHK, CSW and YTH interpreted the results and critically revised the draft. All authors reviewed and approved the final manuscript. SHW is responsible for the integrity of the work as a whole.

Corresponding author

Correspondence to Shi-Heng Wang.

Additional information

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