Genomewide association studies (GWASs) have contributed greatly to unraveling the genetic basis of Alzheimer’s disease (AD). However, a large amount of “missing heritability” remains. In this exploratory study, we investigated the effect of cytosine-adenine-guanine (CAG) repeats in polyglutamine disease-associated genes (PDAGs) on the risk of AD and its expression. In a cohort of 959 patients diagnosed with AD (Amsterdam Dementia cohort) and 4106 cognitively healthy participants (Leiden 85-plus Study and the Prospective Study of Pravastatin in the Elderly at Risk), we determined the CAG repeat sequences in ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR. We did not find a significant association between the risk of AD and variations in CAG repeat numbers of PDAGs. However, we found that differences in CAG repeat numbers in ATXN1, ATXN2, and AR were significantly associated with several clinical and imaging features in AD patients. Specifically, the association between memory performance in patients with AD and the CAG repeat size in the longer ATXN1 allele, and the association between atrophy in the medial temporal lobes and the CAG repeat number in the longer AR allele remained significant after correction for multiple testing. Our findings suggest that repeat polymorphisms in ATXN1 and AR can act as important genetic modifiers of AD, warranting further scrutiny of their role in its missing heritability and pathogenesis.

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Overview publication

TitleRepeat length variations in ATXN1 and AR modify disease expression in Alzheimer’s disease.
DateJanuary 1st, 2019
Issue nameNeurobiology of aging
Issue numberv73:230.e9-230.e17
DOI10.1016/j.neurobiolaging.2018.09.007
PubMed30314815
AuthorsGardiner SL, Harder AVE, Campman YJM, Trompet S, Gussekloo J, van Belzen MJ, Boogaard MW, Roos RAC, Jansen IE, Pijnenburg YAL, Scheltens P, van der Flier WM & Aziz NA
KeywordsAlzheimer's disease, CAG repeat polymorphisms, Huntington disease, Missing heritability, Polyglutamine diseases
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