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

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 da...

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Veröffentlicht in:International Journal of Obesity Jg. 43; H. 3; S. 440 - 449
Hauptverfasser: Gardiner, Sarah L, de Mutsert, Renée, Trompet, Stella, Boogaard, Merel W, van Dijk, Ko Willems, Jukema, P J Wouter, Slagboom, P Eline, Roos, Raymund A C, Pijl, Hanno, Rosendaal, Frits R, Aziz, N Ahmad
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.03.2019
Schlagworte:
Adenine
Aged
Aged, 80 and over
Body Mass Index
Body size
Brain
Central Nervous System Diseases - genetics
Cohort Studies
Cytosine
Deoxyribonucleic acid
DNA
Female
Genes
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomic analysis
Guanine
Heritability
Humans
Male
Middle Aged
Obesity
Obesity - epidemiology
Obesity - genetics
Peptides
Polyglutamine diseases
Polymorphism, Genetic - genetics
Repetitive Sequences, Nucleic Acid - genetics
Risk analysis
Risk factors
Systematic review
Trinucleotide repeat diseases
Trinucleotide repeats
Variation
ISSN:0307-0565, 1476-5497, 1476-5497
Online-Zugang:Volltext
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Zusammenfassung: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. 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. 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. 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.
Bibliographie:ObjectType-Article-1
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ISSN:0307-0565
1476-5497
1476-5497
DOI:10.1038/s41366-018-0161-7