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A modifier of Huntington's disease onset at the MLH1 locus
Jong-Min Lee1,2,3, Michael J Chao1,2, Denise Harold4
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Insights
Genetic factors influence Huntington's disease (HD) onset. A variant near MLH1 delays motor symptoms by 0.7 years per allele, offering a potential therapeutic target for this neurodegenerative disease.
Area of Science:
- Neurogenetics
- Genomics
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder inherited dominantly, primarily caused by expanded CAG repeats in the HTT gene.
- While CAG repeat size is a major determinant of HD clinical features like motor onset age, other genetic factors are increasingly recognized as modifiers.
- Previous genome-wide association studies identified potential modifier loci on chromosomes 8, 15, and 3.
Purpose of the Study:
- To validate and identify genetic modifiers influencing the age of motor onset in Huntington's disease.
- To pinpoint specific functional variants and genes responsible for modifying HD pathogenesis.
- To explore the potential mechanisms by which these genetic modifiers affect disease progression.
Main Methods:
- Genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 HD subjects.
- Genome-wide association analysis to confirm and identify modifier loci.
- Genomic DNA capture and sequencing to localize functional variants within identified loci.
- Expression Quantitative Trait Loci (eQTL) analysis to assess gene regulation.
Main Results:
- Independent confirmation of modifier loci on chromosomes 8 and 15, and genome-wide significance for a locus on chromosome 3 at MLH1.
- Identification of a functional variant in MLH1, present in ~32% of chromosomes, associated with a 0.7-year delay in HD motor onset per allele.
- Localization of the functional variation to a 78kb region spanning MLH1 and LRRFIP2, including an isoleucine-valine missense variant in MLH1.
- eQTL analysis suggested potential altered regulation of both MLH1 and LRRFIP2.
Conclusions:
- Genetic modifiers significantly influence Huntington's disease onset age, with a variant near MLH1 providing a substantial protective effect.
- The identified MLH1 variant and its associated region represent a promising target for understanding and potentially treating HD.
- Further comprehensive genetic analyses in larger HD cohorts are warranted to uncover additional genetic modifiers.
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.