A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes.

ABSTRACT: BACKGROUND:Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. METHODS:The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. FINDINGS:Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI?=?1·94 to 4·80, p?=?1·3 × 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR?=?4·8?×?10-6), MLH3 (pFDR?=?8·0?×?10-4), MLH1 (pFDR?=?0·004) and MSH3 (pFDR?=?0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. INTERPRETATION:These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. FUNDING:CHDI Foundation.

SUBMITTER: Ciosi M 

PROVIDER: S-EPMC6838430 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature