C04 Protein coding tandem repeat in TCERG1 modifies huntington’s disease onset

Background The length of the HTT CAG repeat explains around 60% of the variance in Huntington’s disease (HD) age at onset. Recently, genome-wide association studies (GWAS) of HD age at onset have identified multiple single nucleotide variants (SNVs) that influence onset, including an intronic SNV, rs79727797, in TCERG1 (p=3.76E-10). Aims Since the SNV does not modify the protein or appear to change gene expression, we tested whether the GWAS signal is due to genetic variation not present in the GWAS. Methods/Techniques We developed a novel method for calling perfect and imperfect short tandem repeats from whole exome sequencing (WES) data, and applied it to 610 WES samples from HD individuals with age at onset or cognitive test data discrepant from those predicted by their HTT CAG length. We identified an exonic (CAGGCC)n short tandem repeat in TCERG1 previously reported to be associated with altered HD age at onset. The reference allele is (CAGGCC)6. We identified 5 length alleles with 3 to 8 hexamer repeats. Results/Outcome Reduced repeat length is significantly associated with later HD age-at-onset (sum of repeat from both TCERG1 repeat alleles: p=6.51E-9). The (CAGGCC)3 allele (frequency 4.1%) is in linkage disequilibrium (r2=0.98) with the minor allele at rs79727797, associated with later onset in the GWAS. Conditioning the association of rs79727797 on TCERG1 (CAGGCC)n length reduces its significance from p=2.4E-6 to p=0.96, while STR length is still significantly associated with HD age at onset after conditioning on rs79727797 (p=3.9E-4). This indicates that the repeat, rather than rs79727797, is responsible for the association at this locus. Conclusion The GWAS signal in TCERG1 is attributable to a short tandem repeat, rather than SNVs. Further biological study of the mechanism by which it alters HD age at onset is warranted.