Dataset Information

The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.

ABSTRACT: BACKGROUND:Huntington's disease (HD) is a dominantly inherited disease caused by a CAG expansion mutation in HTT. The age at onset of clinical symptoms is determined primarily by the length of this CAG expansion but is also influenced by other genetic and/or environmental factors. OBJECTIVE:Recently, through genome-wide association studies (GWAS) aimed at discovering genetic modifiers, we identified loci associated with age at onset of motor signs that are significant at the genome-wide level. However, many additional HD modifiers may exist but may not have achieved statistical significance due to limited power. METHODS:In order to disseminate broadly the entire GWAS results and make them available to complement alternative approaches, we have developed the internet website "GeM MOA" where genetic association results can be searched by gene name, SNP ID, or genomic coordinates of a region of interest. RESULTS:Users of the Genetic Modifiers of Motor Onset Age (GeM MOA) site can therefore examine support for association between any gene region and age at onset of HD motor signs. GeM MOA's interactive interface also allows users to navigate the surrounding region and to obtain association p-values for individual SNPs. CONCLUSIONS:Our website conveys a comprehensive view of the genetic landscape of modifiers of HD from the existing GWAS, and will provide the means to evaluate the potential influence of genes of interest on the onset of HD. GeM MOA is freely available at https://www.hdinhd.org/.

SUBMITTER: Correia K

PROVIDER: S-EPMC4753529 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.

Correia Kevin K Harold Denise D Kim Kyung-Hee KH Holmans Peter P Jones Lesley L Orth Michael M Myers Richard H RH Kwak Seung S Wheeler Vanessa C VC MacDonald Marcy E ME Gusella James F JF Lee Jong-Min JM

Journal of Huntington's disease 20150101 3

<h4>Background</h4>Huntington's disease (HD) is a dominantly inherited disease caused by a CAG expansion mutation in HTT. The age at onset of clinical symptoms is determined primarily by the length of this CAG expansion but is also influenced by other genetic and/or environmental factors.<h4>Objective</h4>Recently, through genome-wide association studies (GWAS) aimed at discovering genetic modifiers, we identified loci associated with age at onset of motor signs that are significant at the genom ...[more]

PMID: 26444025

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Project description:The ability to finely control our movement is key to achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown. Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature. Here we present the first genome-wide association study to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children, providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N = 4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance, however, 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNPs, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20, and ADAM21. Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.

Project description:<p>Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by expansion of an otherwise polymorphic CAG trinucleotide repeat. The mutation causes a gain-of-function of the huntingtin protein to trigger a pathogenic process that produces detectable phenotypic differences many years before the traditional diagnosis, which is based upon characteristic motor symptoms. The prediagnosis phase of pathogenesis is now the subject of intense scrutiny by an NINDS-funded longitudinal study, PREDICT-HD, in which undiagnosed gene carriers are followed longitudinally and subjected to detailed phenotyping (PREDICT-HD Huntington Disease Study -- dbGaP Study Accession: <a href="./study.cgi?study_id=phs000222">phs000222</a>). This powerful approach, which offers the potential for moving the focus of therapeutic development to the decades prior to neurological disease diagnosis, is enabled by the fact that all individuals with HD have the same type of mutation, which can be determined at any time in life by a single HD CAG repeat PCR amplification assay. The precise length of the HD CAG repeat differs between individuals. There is a strong negative correlation between the number of CAG repeats and the age at onset of diagnostic neurological abnormalities in HD, such that the CAG repeat accounts for ~50% of the variation in age at diagnosis. Analysis of the remaining variance not explained by the length of the CAG repeat has shown that it is highly heritable, being due to genetic variation, elsewhere in the genome.</p> <p>The intent of the Genetic Modifiers of Huntington's Disease study is to identify genetic modifiers of HD pathogenesis by using genomewide association techniques in diagnosed HD individuals to identify genetic factors associated with the residual variance in age at onset not explained by the CAG repeat, and to extend these analyses to pre-diagnosis phenotypes, for example, those defined in the PREDICT-HD study. Identification of modifier genes is a top priority for HD research (and an example of an approach that can be applied in other late-onset genetic disorders), as it could provide clues to developing rational treatments that delay or prevent the pathogenic process from causing the ravages of the disease that ensue in the ~15 years of inexorable decline to ultimate death that now follows clinical diagnosis.</p>

Dataset Information

The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.

Publications

The Genetic Modifiers of Motor OnsetAge (GeM MOA) Website: Genome-wide Association Analysis for Genetic Modifiers of Huntington's Disease.

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