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Genetics and Epigenetics

Repeat length variations in polyglutamine disease-associated genes affect body mass index

Abstract

Background

The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this ‘missing heritability’ problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS.

Subjects and methods

We determined the cytosine–adenine–guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models.

Results

We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation.

Conclusions

Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.

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Acknowledgements

We would like to express our gratitude to all individuals who participated in the NEO and PROSPER study as well as all research staff for collecting the data and I. de Jonge for data management. Dr. Anton de Craen’s guidance was crucial for the design of this study for which we posthumously wish to express our utmost appreciation. This study was supported by a VENI-grant (#91615080) from the Netherlands Organization of Scientific Research and a Marie Sklodowska-Curie Individual Fellowship grant from the European Union (Horizon 2020, #701130; NAA). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine’.

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Correspondence to Sarah L. Gardiner.

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