Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

Abstract

Background: Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. Methods: We developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington's disease via regression analysis. Results: We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1x10-9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. Conclusions: The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.

Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington’s disease

“…We also detected dysregulated splicing in the TCERG1 gene, a regulator of transcriptional elongation and pre-mRNA splicing, in both IsoHD and HD striatum. TCERG1 has been identified as a genetic modifier of age of onset in HD, where the length of a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 is inversely correlated with age at the onset of symptoms 26,32 . In our results, we found that the decreased inclusion of an adjacent retained intron and exon 6 in the TCERG1 transcripts is associated with CAG length, although not monotonically.…”

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects

“…The up-or downpointing orientation of the triangle indicates the direction of effect, and the triangle size reflects the SNV MAF. We previously described a delaying age at motor onset modifier effect (5BM1), tagged by rs79727797, and subsequently attributed modification to the length of a quasi-tandem hexamer repeat encoding a glutamine/alanine tract in TCERG1 (Lobanov et al, 2022). This SNV tag (red in Figure 1B) showed the greatest significance (age at motor onset: p=8.9E-14; age at TFC6: p=1.8E-18), but conditional analyses in the age at TFC6 GWAS revealed a second modifier haplotype of significant SNVs spanning TCERG1 (blue triangles in Figure 1B).…”

“…Conditioning the age at TFC6 analysis on either of the two 5BM1 or 5BM2 tag SNVs increased the significance for the other, and simultaneously conditioning on both SNVs eliminated all suggestive significant signals. The 5BM2 modifier is not associated with length variation in the TCERG1 hexamer repeat, being present only on chromosomes with the most frequent repeat length (91% of alleles) in the exome data used previously to analyze 5BM1 (Lobanov et al, 2022). 5BM2 tag SNVs do not reveal significant expression quantitative trait locus (eQTL) or splicing quantitative trait locus (sQTL) signals in brain in the GTEx database (https://www.gtexportal.org/home/aboutAdultGtex).…”