Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease.
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ABSTRACT:
SUBMITTER: Ruiz-Martinez J
PROVIDER: S-EPMC5540655 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
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Whole-exome sequencing associates novel <i>CSMD1</i> gene mutations with familial Parkinson disease.
Ruiz-Martínez Javier J Azcona Luis J LJ Bergareche Alberto A Martí-Massó Jose F JF Paisán-Ruiz Coro C
Neurology. Genetics 20170802 5
<h4>Objective</h4>Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.<h4>Methods</h4>In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.<h4>Results< ...[more]
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Project description:ImportanceParkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.ObjectiveTo identify genetic variants contributing to disease risk in familial PD.Design, setting, and participantsA 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.Main outcomes and measuresIdentification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.ResultsThe 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.Conclusions and relevanceTNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.
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Project description:Background: Mood disorder is ranked seventh among the worldwide causes of non-fatal disease burden and is generally believed to be a heritable disease. However, there is still a substantial portion of the heritability yet to be discovered, despite the success of genome-wide association studies (GWAS) for mood disorder. A proportion of the missing heritability may be accounted for by rare coding variants segregating in families enriched with mood disorder. Methods: To identify novel variants segregating with mood disorder, we performed whole-exome sequencing on genomic DNA for a multigenerational family with nine members affected with mood disorder. We prioritized potential causal variants within the family based on segregation with mood disorder, predicted functional effects, and prevalence in human populations. In addition, for the top-ranked candidate variant, we conducted validation in vivo to explore the pathogenesis of mood disorder. Results: We identified and ranked 26 candidate variants based on their segregation pattern and functional annotations. The top-ranked variant, rs78809014, is located in intron 7 of the MAPKAP1 gene. The expression levels of MAPKAP1 in peripheral blood of both major depression disorder (MDD) patients and depressive-like mice ventral dentate gyrus were significantly higher than that in the corresponding controls. In addition, the expression level of MAPKAP1 were correlated with antidepressant response. Conclusions: Although the exact mechanisms in the family remain to be elucidated, our data strongly indicate a probable role of the variant, rs78809014, in the regulatory process of the expression of MAPKAP1 and thus in the development of mood disorder in familial mood disorder.
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