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A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p?=?2.97?×?10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p?=?1.82?×?10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p?=?7.81?×?10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

SUBMITTER: Nakamura R

PROVIDER: S-EPMC7511394 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

Nakamura Ryoichi R Misawa Kazuharu K Tohnai Genki G Nakatochi Masahiro M Furuhashi Sho S Atsuta Naoki N Hayashi Naoki N Yokoi Daichi D Watanabe Hazuki H Watanabe Hirohisa H Katsuno Masahisa M Izumi Yuishin Y Kanai Kazuaki K Hattori Nobutaka N Morita Mitsuya M Taniguchi Akira A Kano Osamu O Oda Masaya M Shibuya Kazumoto K Kuwabara Satoshi S Suzuki Naoki N Aoki Masashi M Ohta Yasuyuki Y Yamashita Toru T Abe Koji K Hashimoto Rina R Aiba Ikuko I Okamoto Koichi K Mizoguchi Kouichi K Hasegawa Kazuko K Okada Yohei Y Ishihara Tomohiko T Onodera Osamu O Nakashima Kenji K Kaji Ryuji R Kamatani Yoichiro Y Ikegawa Shiro S Momozawa Yukihide Y Kubo Michiaki M Ishida Noriko N Minegishi Naoko N Nagasaki Masao M Sobue Gen G

Communications biology 20200923 1

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant associa ...[more]

PMID: 32968195

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Project description:Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.

Dataset Information

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

Publications

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

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