Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-03 DOI:10.1007/s00439-024-02704-y

Kelsey Robinson, Randy Parrish, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Jeffrey C Murray, Gary M Shaw, Seth M Weinberg, Harrison Brand, Mary L Marazita, David J Cutler, Michael P Epstein, Jingjing Yang, Elizabeth J Leslie

{"title":"Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.","authors":"Kelsey Robinson, Randy Parrish, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Jeffrey C Murray, Gary M Shaw, Seth M Weinberg, Harrison Brand, Mary L Marazita, David J Cutler, Michael P Epstein, Jingjing Yang, Elizabeth J Leslie","doi":"10.1007/s00439-024-02704-y","DOIUrl":null,"url":null,"abstract":"Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G × S) interaction testing. There were 13 loci significant for G × S interactions, with the top finding in LTBP1 (RR = 3.37 [2.04-5.56], p = 1.93 × 10-6). LTBP1 plays a role in regulating TGF-β bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G × S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p = 0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1341-1352"},"PeriodicalIF":3.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00439-024-02704-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/3 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G × S) interaction testing. There were 13 loci significant for G × S interactions, with the top finding in LTBP1 (RR = 3.37 [2.04-5.56], p = 1.93 × 10^-6). LTBP1 plays a role in regulating TGF-β bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G × S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p = 0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

查看原文本刊更多论文

基因与性别相互作用的全基因组研究确定了腭裂的风险。

结构性出生缺陷占所有活产婴儿的 3-4%，而且根据类型的不同，往往表现为性别差异。腭裂是最常见的颅面部结构性出生缺陷，通常分为唇裂伴或不伴腭裂（CL/P）和单纯腭裂（CP）。以往的研究发现，唇裂伴或不伴腭裂（CL/P）有性别特异性风险，但这些风险尚未在 CP 中进行评估。CL/P 多见于男性，而 CP 多见于女性，因此我们假设 CP 也存在性别差异。我们使用一个基于三人的队列，根据原告性别进行了性别分层全基因组关联研究（GWAS），然后进行了全基因组基因与性别（G × S）交互检验。有 13 个基因位点存在明显的 G × S 相互作用，其中发现最多的是 LTBP1（RR = 3.37 [2.04-5.56], p = 1.93 × 10-6）。LTBP1 在调节 TGF-β 生物利用率方面发挥作用，在小鼠和斑马鱼中敲除 LTBP1 会导致颅面畸形。此外，有证据表明，在小鼠和人类中，LTBP1 在雌雄之间的表达存在差异。因此，我们检测了具有显著 G × S 相互作用的基因的推算遗传调控基因表达与 CP 表型之间的关联。我们发现，雌性受试者细胞培养成纤维细胞中的 LTBP1 与 CP 表型有明显关联（p = 0.0013），而雄性受试者则没有。总之，我们的研究表明，CP 存在性别特异性风险，而这些风险在性别组合队列中是检测不到的，LTBP1 是一个候选风险基因，尤其是在女性中。

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 Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.