Identifying X-chromosome variants associated with age-related macular degeneration.

IF 3.1 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Human molecular genetics Pub Date : 2024-12-06 DOI:10.1093/hmg/ddae141

Michelle Grunin, Robert P Igo, Yeunjoo E Song, Susan H Blanton, Margaret A Pericak-Vance, Jonathan L Haines

{"title":"Identifying X-chromosome variants associated with age-related macular degeneration.","authors":"Michelle Grunin, Robert P Igo, Yeunjoo E Song, Susan H Blanton, Margaret A Pericak-Vance, Jonathan L Haines","doi":"10.1093/hmg/ddae141","DOIUrl":null,"url":null,"abstract":"Purpose: In genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous GWAS identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore¸ our goal was to investigate ChrX variants for association with AMD.Methods: We genotyped 29 629 non-Hispanic White (NHW) individuals (M/F:10404/18865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1 221 623 variants on ChrX. Age, informative PCs, and subphenotypes were covariates for logistic association analyses with Fisher's correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath.Results: Logistic association on NHW individuals with sex correction identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P < 1 × 10-6,Fisher's combined-corrected). Association testing of the subphenotypes of choroidal neovascularization and geographic atrophy (GA), identified variants in DMD associated with GA (P < 1 × 10-6, Fisher's combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P < 0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9. Pathway analysis using GSEASNP and DAVID identified genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P < 0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs showed association with brain disorders and fatty acid elongation (P < 0.05). A long noncoding RNA on ChrX near the DMD locus was also associated with AMD (P = 4 × 10-7). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P = 2 × 10^-5).Conclusions: Analysis of ChrX variation identifies several potential new locifor AMD risk and these variants nominate novel AMD pathways. Further analysis is needed to refine these results and to understand their biological significance and relationship with AMD development in worldwide populations.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"2085-2093"},"PeriodicalIF":3.1000,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630753/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human molecular genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/hmg/ddae141","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: In genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous GWAS identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore¸ our goal was to investigate ChrX variants for association with AMD.

Methods: We genotyped 29 629 non-Hispanic White (NHW) individuals (M/F:10404/18865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1 221 623 variants on ChrX. Age, informative PCs, and subphenotypes were covariates for logistic association analyses with Fisher's correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath.

Results: Logistic association on NHW individuals with sex correction identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P < 1 × 10-6,Fisher's combined-corrected). Association testing of the subphenotypes of choroidal neovascularization and geographic atrophy (GA), identified variants in DMD associated with GA (P < 1 × 10-6, Fisher's combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P < 0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9. Pathway analysis using GSEASNP and DAVID identified genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P < 0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs showed association with brain disorders and fatty acid elongation (P < 0.05). A long noncoding RNA on ChrX near the DMD locus was also associated with AMD (P = 4 × 10-7). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P = 2 × 10^-5).

Conclusions: Analysis of ChrX variation identifies several potential new locifor AMD risk and these variants nominate novel AMD pathways. Further analysis is needed to refine these results and to understand their biological significance and relationship with AMD development in worldwide populations.

查看原文本刊更多论文

识别与老年性黄斑变性相关的 X 染色体变异。

目的：在全基因组关联研究（GWAS）中，X 染色体（ChrX）变异往往未被调查。研究这些效应需要性别特异性效应和 ChrX 特异性质量控制（QC）。之前的 GWAS 通过国际 AMD 基因组学联合会（IAMDGC）发现了 52 个与年龄相关性黄斑变性（AMD）有关的常染色体变异，但没有对 ChrX 进行分析。因此，我们的目标是研究 ChrX 变异与 AMD 的关系：我们通过定制芯片对 29 629 名非西班牙裔白人（NHW）进行了基因分型（男/女：10404/18865；AMD12,087/14723），并使用密歇根推算服务器（Michigan Imputation Server）对 ChrX 特异性 QC（XWAS 3.0）进行了推算。推算产生了 1 221 623 个 ChrX 变异。年龄、信息 PCs 和亚表型是经费雪校正进行逻辑关联分析的协变量。基因/通路分析使用 VEGAS、GSEASNP、ICSNPathway、DAVID 和 mirPath 进行：对 NHW 个体进行性别校正后的逻辑关联分析发现了 SLITRK4、ARHGAP6、FGF13 和 DMD 基因中/附近与 AMD 相关的变异（P 结论：对 ChrX 变异的分析发现了与 AMD 相关的变异：对 ChrX 变异的分析确定了几个潜在的 AMD 风险新位点，这些变异提名了新的 AMD 通路。需要进一步分析以完善这些结果，并了解它们的生物学意义以及与全球人群中 AMD 发展的关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Human molecular genetics 生物-生化与分子生物学

CiteScore

6.90

自引率

2.90%

发文量

294

审稿时长

2-4 weeks

期刊介绍： Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.