通过中重度哮喘全基因组测序识别哮喘风险相关肺功能基因位点
2022/05/17
摘要
背景：全基因组关联分析（GWAS）已确定多个与哮喘易感性相关的常见变异位点，但很少有涉及中重度哮喘风险相关的遗传学研究。
方法：本研究对 3181 名中重度哮喘患者与 3590 名非哮喘对照者进行通过全基因组测序分析及比较。
结果：本研究证实哮喘风险与肺功能指标存在遗传学相关性，且哮喘风险的这一成分与哮喘易感性相关的嗜酸性粒细胞遗传学特征正交。本研究发现肺功能降低多基因评分越高，哮喘发病年龄越早。全基因组中7 个先前报道的常见哮喘变异基因位点和 1 个先前报道的肺功能基因位点，接近 THSD4，具有统计学显着性。本研究在近期发表的中重度哮喘患者的 GWAS 中也重复了这一肺功能基因位点相关性。本研究还重复分析先前报道的 IL33 中罕见（次要等位基因频率＜1%）编码变异位点的关联性，结果显示常见变应性疾病基因座的基因中，罕见变异基因显著富集。
结论：本研究结果强调了肺功能基因变异对中重度哮喘风险的贡献，并初步提出罕见变异位点支持常见变异位点中的多个候选基因与中重度哮喘风险之间存在相关性。
A whole genome sequencing study of moderate to severe asthma identifies a lung function locus associated with asthma risk.
Chang D, Hunkapiller J, Bhangale T, Reeder J, Mukhyala K, Tom J, Cowgill A, Vogel J, Forrest WF, Khan Z, Stockwell A, McCarthy MI, Staton TL, Olsson J, Holweg CTJ, Cheung DS, Chen H, Brauer MJ, Graham RR, Behrens T, Wilson MS, Arron JR, Choy DF, Yaspan BL.
Abstract
BACKGROUND:Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk.
METHODS:Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls.
RESULTS:We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci.
CONCLUSIONS:Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.
背景：全基因组关联分析（GWAS）已确定多个与哮喘易感性相关的常见变异位点，但很少有涉及中重度哮喘风险相关的遗传学研究。
方法：本研究对 3181 名中重度哮喘患者与 3590 名非哮喘对照者进行通过全基因组测序分析及比较。
结果：本研究证实哮喘风险与肺功能指标存在遗传学相关性，且哮喘风险的这一成分与哮喘易感性相关的嗜酸性粒细胞遗传学特征正交。本研究发现肺功能降低多基因评分越高，哮喘发病年龄越早。全基因组中7 个先前报道的常见哮喘变异基因位点和 1 个先前报道的肺功能基因位点，接近 THSD4，具有统计学显着性。本研究在近期发表的中重度哮喘患者的 GWAS 中也重复了这一肺功能基因位点相关性。本研究还重复分析先前报道的 IL33 中罕见（次要等位基因频率＜1%）编码变异位点的关联性，结果显示常见变应性疾病基因座的基因中，罕见变异基因显著富集。
结论：本研究结果强调了肺功能基因变异对中重度哮喘风险的贡献，并初步提出罕见变异位点支持常见变异位点中的多个候选基因与中重度哮喘风险之间存在相关性。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Sci Rep. 2022 Apr 2;12(1):5574. doi: 10.1038/s41598-022-09447-8.)
(Sci Rep. 2022 Apr 2;12(1):5574. doi: 10.1038/s41598-022-09447-8.)
A whole genome sequencing study of moderate to severe asthma identifies a lung function locus associated with asthma risk.
Chang D, Hunkapiller J, Bhangale T, Reeder J, Mukhyala K, Tom J, Cowgill A, Vogel J, Forrest WF, Khan Z, Stockwell A, McCarthy MI, Staton TL, Olsson J, Holweg CTJ, Cheung DS, Chen H, Brauer MJ, Graham RR, Behrens T, Wilson MS, Arron JR, Choy DF, Yaspan BL.
Abstract
BACKGROUND:Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk.
METHODS:Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls.
RESULTS:We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci.
CONCLUSIONS:Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci.
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