Dataset Information

Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.

ABSTRACT: Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also reanalyzed previous data from genome-wide association studies (GWAS) on the same cohort. Variants in the CEL gene/locus were associated with PD in both GWAS and WES analysis. Exome-wide gene-based association tests also identified the MPHOSPH10, TAS2R19, and SERPINA1 genes in the discovery data set (p < 2.5E-6). MPHOSPH10 had estimated odds ratio (OR) of 1.53, and the rs141620200 variant in SERPINA1 had OR of 1.27. We identified several candidate genes, but further investigation is required to determine the role of these genes in PD.

SUBMITTER: Siitonen A

PROVIDER: S-EPMC5385296 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.

Siitonen Ari A Nalls Michael A MA Hernández Dena D Gibbs J Raphael JR Ding Jinhui J Ylikotila Pauli P Edsall Connor C Singleton Andrew A Majamaa Kari K

Neurobiology of aging 20170202

Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also reanalyzed previous data from genome-wide association studies (GWAS) on the ...[more]

PMID: 28256260

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Project description:BackgroundColorectal cancer (CRC) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi-allelic autosomal recessive pathogenic variants.MethodsThe cohort was whole exome sequenced (WES) at 100× coverage. Both a dominant- and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young-onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss-of-function) or allele frequency.ResultsWe identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes (BMPR1A, BRIP1, and SRC), three truncating variants in possibly novel cancer genes (CLSPN, SEC24B, SSH2) and four candidate missense variants in ACACA, NR2C2, INPP4A, and DIDO1. We also identify five possible autosomal recessive candidate genes: ATP10B, PKHD1, UGGT2, MYH13, TFF3.ConclusionTwo clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

Dataset Information

Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.

Publications

Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.

Similar Datasets

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