Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease–Associated Alleles Among Large Population-Based Cohorts

Importance Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective To determine the prevalence of carriers of intermediate and pathological polyglutamine disease–associated alleles among the general population. Design, Setting, and Participants This observational cross-sectional study included data from 5 large European population–based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease–associated genes (PDAGs) (ie, ATXN1 , ATXN2 , ATXN3 , CACNA1A , ATXN7 , TBP , HTT , ATN1 , and AR ) was determined. Exposure The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease–associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.