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Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis.

ABSTRACT: Genome-wide association studies (GWAS) have identified multiple causal genes associated with amyotrophic lateral sclerosis (ALS); however, the genetic architecture of ALS remains completely unknown and a large number of causal genes have yet been discovered. To full such gap in part, we implemented an integrative analysis of transcriptome-wide association study (TWAS) for ALS to prioritize causal genes with summary statistics from 80,610 European individuals and employed 13 GTEx brain tissues as reference transcriptome panels. The summary-level TWAS analysis with single brain tissue was first undertaken and then a flexible p-value combination strategy, called summary data-based Cauchy Aggregation TWAS (SCAT), was proposed to pool association signals from single-tissue TWAS analysis while protecting against highly positive correlation among tests. Extensive simulations demonstrated SCAT can produce well-calibrated p-value for the control of type I error and was often much more powerful to identify association signals across various scenarios compared with single-tissue TWAS analysis. Using SCAT, we replicated three ALS-associated genes (i.e., ATXN3, SCFD1, and C9orf72) identified in previous GWASs and discovered additional five genes (i.e., SLC9A8, FAM66D, TRIP11, JUP, and RP11-529H20.6) which were not reported before. Furthermore, we discovered the five associations were largely driven by genes themselves and thus might be new genes which were likely related to the risk of ALS. However, further investigations are warranted to verify these results and untangle the pathophysiological function of the genes in developing ALS.

SUBMITTER: Xiao L

PROVIDER: S-EPMC7714931 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis.

Xiao Lishun L Yuan Zhongshang Z Jin Siyi S Wang Ting T Huang Shuiping S Zeng Ping P

Frontiers in genetics 20201120

Genome-wide association studies (GWAS) have identified multiple causal genes associated with amyotrophic lateral sclerosis (ALS); however, the genetic architecture of ALS remains completely unknown and a large number of causal genes have yet been discovered. To full such gap in part, we implemented an integrative analysis of transcriptome-wide association study (TWAS) for ALS to prioritize causal genes with summary statistics from 80,610 European individuals and employed 13 GTEx brain tissues as ...[more]

PMID: 33329728

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Project description:The cause of sporadic amyotrophic lateral sclerosis (ALS) is unknown. To identify the genetic factors underlying this fatal neurodegenerative disease, we performed a series of genome-wide association studies of ALS. These studies are divided into three distinct stages, each associated with a separate data release. A description of each stage is provided below. In the first stage, we genotyped 555,352 SNPs in 276 US cases diagnosed with ALS and 271 US controls. These samples were obtained from the National Institute of Neurological Disorders and Stroke (NINDS) DNA Repository at Coriell. The 276 US cases were genotyped on Illumina HumanHap550v1.1 SNP arrays, whereas the 271 US controls were genotyped on both Illumina HumanHap250Sv1.0 and Illumina HumanHap300v1.1 SNP arrays. The genotype data was released in June 2008 under the accession number <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a> and was associated with the following publication: Schymick JC et al. (2007) <a href="http://www.ncbi.nlm.nih.gov/pubmed/17362836" target="_blank">Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data</a>. Lancet Neurology 6:322-8. In the second stage, we extended our genotyping to a larger cohort to identify risk factors with lower effect size. This portion of the project used a two-step approach: in step A, 545,066 SNPs were genotyped in 553 individuals with ALS and 2,338 controls. Of note, this cohort included data from the 276 US cases and 271 US controls that had been previously released in the first stage, <a href="./study.cgi?study_id=phs000101.v1.p1">phs000101.v1.p1</a>. The additional 277 ALS cases that were newly genotyped in this stage were collected in a population-based manner from the North of Italy and were genotyped on Illumina HumanHap550v1.1 SNP arrays. In step B, we brought forward the 7,600 most associated SNPs from step A, and genotyped them in an additional cohort consisting of 2,160 cases and 3,008 controls using an Illumina iSelect custom designed SNP array. The new data generated from this study was released in May 2010 (<a href="./study.cgi?study_id=phs000101.v2.p1">phs000101.v2.p1</a>) and consisted of 1,456 case samples and 773 control samples for which participants provided consent to make their data publicly available. We do not have permission to publicly release the genotype data from the rest of the samples. This data release was associated with the following publication: Chiò A et al. (2009) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19193627" target="_blank">A two-stage genome wide association study of sporadic amyotrophic lateral sclerosis</a>. Human Molecular Genetics 18:1524-32. In the third stage, we genotyped 601,273 SNPs in an additional set of 236 Italian ALS cases. Together with the 264 Italian samples genotyped as part of stage 2, this brought the total number of samples that were whole genome genotyped samples to 504. These additional 236 patients had been collected in a population-based manner from the Piedmonte region in the North of Italy, and were genotyped using Illumina Human610Quad.v1 SNP arrays. The rational for this stage of the study arose from a Proceedings of the National Academy of Sciences (PNAS) publication by Landers et al. 2009, hypothesizing that genetic variation on chromosome 1q24 in the vicinity of the KIFAP3 gene was associated with a significant improvement in survival of ALS patients. Our data failed to replicate this finding suggesting that the original finding may have been a false positive finding. The data generated for the extra 236 Italian ALS cases used in this study was released in April 2011 (<a href="./study.cgi?study_id=phs000101.v3.p1">phs000101.v3.p1</a>). This data release was associated with the following publication: Traynor BJ et al. (2010) <a href="http://www.ncbi.nlm.nih.gov/pubmed/20566859" target="_blank">Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients</a>. PNAS 107:12335-8. Of note, 95 of these 236 samples had also been genotyped on the Illumina iSelect custom designed SNP array used in the second stage of this study (see README.txt file available through dbGaP Authorized Access for list of the 95 samples). This study utilized the <a href="./study.cgi?id=phs000006">NINDS Repository Motor Neuron Disease/ALS Study</a>, and <a href="./study.cgi?id=phs000004">neurologically normal controls</a> from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection.

Project description:ImportanceConsiderable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.ObjectiveTo estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.Design, setting, and participantsWe applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.Main outcomes and measuresA linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.ResultsWith our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.Conclusions and relevanceWe found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.

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Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis.

Publications

Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis.

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