DOI: 10.5061/dryad.3xsj3txpx
title: Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects

description: An inherited, expanded CAG repeat in HTT undergoes further somatic
 expansion to cause Huntington’s disease (HD).  To gain insights
 into this molecular mechanism, we compared genome-wide association studies
 of somatic expansion in blood and somatic expansion-driven HD clinical
 phenotypes.  Here, we show that somatic expansion is driven by a
 mismatch repair-related process whose genetic modification and
 consequences show unexpected complexity, including cell-type
 specificity.  The HD clinical trajectory is further modified by
 non-DNA repair genes that differentially influence measures of cognitive
 and motor dysfunction.  In addition to shared (DNA repair genes
 MSH3, PMS2, and FAN1) and distinct trans-modifiers, a synonymous
 CAG-adjacent variant in HTT dramatically hastens motor onset without
 increasing somatic expansion, while a cis-acting 5’-UTR variant promotes
 blood repeat expansion without influencing clinical HD.  Our
 findings are directly relevant to the therapeutic suppression of expansion
 in DNA repeat disorders and provide additional clues to HD pathogenic
 mechanisms beyond somatic expansion.
description: The typed genotype data from HD subjects were subject to quality
 control (QC) such as call rate &lt; 95% or minor allele frequency
 &lt; 1% for subsequent pre-imputation QC  using the "HRC or 1000G
 Imputation preparation and checking" program
 (https://www.chg.ox.ac.uk/~wrayner/tools/; Version 4.3.0). Then, genotypes
 were imputed using the TOPMed Imputation Server
 (https://imputation.biodatacatalyst.nhlbi.nih.gov/#!) involving MINIMAC4
 and EAGLE V2.4. The TOPMed r2 was used as the reference panel (i.e., all
 populations). Post-imputation, SNVs with 1) imputation
 r<sup>2</sup> value &lt; 0.5,  2) call rate &lt; 100%,
 3) Hardy-Weinberg equilibrium p value &lt; 1E-6 except for the
 chromosome 4:1-5,000,000 region, or 4) minor allele frequency &lt;
 0.1% were removed. These quality control filters generated approximately
 19,000,000 imputed SNVs for genome-wide association study (GWAS) for
 clinical (age at onset, DCL4, TFC6. TFC6 in Europeans), repeat instability
 (blood instability based on ABI, blood instability based on MiSeq), and
 quantile phenotypes (bradykinesia, chorea, dystonia, oculomotor, rigidity,
 SDMT, stroopword, TMS) in participants. GWAS was based on a mixed effects
 model using the GEMMA program. Summary results for each phenotype GWAS are
 available at the DRYAD.
description: # Genetic modifiers of somatic expansion and clinical phenotypes in
 Huntington’s disease reveal shared and tissue-specific effects Genome-wide
 association study (GWAS) for clinical and molecular phenotypes of
 Huntington's disease was performed, revealing overlapping and
 distinct genetic modifiers of clinical landmarks and somatic expansion in
 blood DNA. Summary results of GWAS of 14 phenotypes are available. **Name
 of the GWAS summary file** In our study, we analyzed three groups of
 phenotypes: * Blood instability phenotypes (2 files) - Clinical phenotypes
 (4 files) * Algorithmically predicted quantile phenotypes (8 files) The
 first part of the GWAS summary file name indicates the phenotype group,
 while the second part specifies the particular phenotype within that
 group. Blood instability phenotypes: We analyzed ABI PPS and MiSeq
 expansion ratio phenotypes. Clinical phenotypes: We examined DCL4, onset,
 and TFC6. For TFC6, we conducted an additional analysis restricted to
 Europeans. Algorithmically predicted quantile phenotypes: We assessed
 bradykinesia, chorea, dystonia, oculomotor function, rigidity, SDMT
 (Symbol Digit Modalities Test), Stroop word, and TMS (Total Motor Score).
 ## Description of the data and file structure Each GWAS summary data
 contains columns for SNP (variant name),  CHR (chromosome),  BP (base
 pair),  SAMPLE_SIZE (sample size), TEST_ALLELE (test allele), BETA (effect
 size of the test allele), SE (standard error), and P (mixed effect model
 association analysis p-value). GWAS summary result file can be opened by
 text editor in the UNIX system and used for meta-analysis and other
 analyses. ## Sharing/Access information Original data will be made
 available on request. Individual level genetic data cannot be deposited
 into a public or controlled repository due to restrictions imposed by the
 General Data Protection Regulation of the European Union and the CHDI
 Foundation, sponsor of the Enroll-HD Platform. They can be obtained by
 qualiﬁed investigators given their institutional assurance of subject
 conﬁdentiality and compliance with GDPR requirements with respect to
 personal data by emailing
 [info@chdifoundation.org](mailto:info@chdifoundation.org) with the words
 ‘‘GWAS123456 data’’ in the subject line. ## Code/Software A standard set
 of analysis programs such as PLINK (genotype QC, data management), GEMMA
 (association analysis), and R (plotting, data management) were used to
 generate the GWAS results. Detailed description of the softwares and codes
 will be available in the published manuscript.