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Hum Mol Genet. 2017 Oct 1;26(19):3859-3867. doi: 10.1093/hmg/ddx286.

A modifier of Huntington's disease onset at the MLH1 locus.

Author information

1
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
2
Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
3
Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA.
4
Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
5
Department of Neurology, Ulm University, 89081 Ulm, Germany.
6
Department of Neurology and Genome Science Institute, Boston University School of Medicine, Boston, MA 02118, USA.
7
CHDI Foundation, Princeton, NJ 08540, USA.
8
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets.

PMID:
28934397
DOI:
10.1093/hmg/ddx286
[Indexed for MEDLINE]

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