慢性阻塞性肺疾病全基因組關(guān)聯(lián)研究進(jìn)展

錢國清

綜 述

慢性阻塞性肺疾病全基因組關(guān)聯(lián)研究進(jìn)展

錢國清1,2,3

1. 寧波大學(xué)附屬寧波市第一醫(yī)院內(nèi)科，寧波 315010 2. 浙江大學(xué)寧波醫(yī)院呼吸科，寧波 315010 3. 英國諾丁漢大學(xué)醫(yī)學(xué)院，諾丁漢 NG7 2RD

慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是一種以不完全可逆的氣流受限為主要特征的慢性氣道炎癥，是一種由遺傳因素和環(huán)境因素共同作用的復(fù)雜疾病，也是世界主要致死疾病之一。近年來，隨著全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)的不斷深入，研究者們發(fā)現(xiàn)了大量與肺功能或COPD相關(guān)的遺傳變異或基因位點、藥物靶點等。本文綜述了2007年以來世界范圍內(nèi)針對肺功能或COPD的GWAS方面的研究工作及其進(jìn)展綜述，分析了可能存在的藥物靶點，并探討了COPD在全基因組關(guān)聯(lián)研究中面臨的挑戰(zhàn)和困難，為深入研究COPD發(fā)病機制提供新思路。

慢性阻塞性肺疾??；肺功能；全基因組關(guān)聯(lián)研究；遺傳變異；基因座；易感基因；致病基因

慢性阻塞性肺疾病(chronic obstructive pulmo-nary disease, COPD)是一種以氣流受限為主要特征的慢性氣道炎癥。肺功能檢查可評估COPD氣流受限程度，當(dāng)吸入支氣管擴張劑后，第一秒用力呼氣容積(forced expiratory volume in one second, FEV1)和用力肺活量(forced vital capacity, FVC)之間比值<0.7表明存在持續(xù)氣流受限，排除其他疾病后，可確診COPD。因此，肺功能是診斷COPD的金標(biāo)準(zhǔn)[1]。據(jù)報道我國40歲以上人群COPD患病率高達(dá)13.7%，總?cè)藬?shù)近1億[2]。2015年，全球預(yù)計有320萬人死于COPD，其中中國有100多萬[3]；根據(jù)世界衛(wèi)生組織預(yù)測，至2020年COPD將成為全球第3大致死疾病[4]。吸煙、空氣污染、職業(yè)暴露等多種因素均可導(dǎo)致COPD，其中吸煙患者僅有10%~20%發(fā)展成為COPD[5]，然而25%的COPD患者終生不吸煙[6]，因此表明，COPD是遺傳因素與環(huán)境因素共同作用的結(jié)果。近年，隨著全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)在肺功能和COPD中的應(yīng)用，發(fā)現(xiàn)了大量易感基因(susceptibility gene)或基因座(locus)，為進(jìn)一步闡述COPD的發(fā)病機制提供了全新的思路。

GWAS研究是在一定人群中選擇病例組和對照組，基于單核苷酸多態(tài)性(single nucleotide polymor-phism, SNP)作為分子遺傳標(biāo)記，比較全基因組范圍內(nèi)所有SNP位點的等位基因或基因型頻率在病例組和對照組間的差異；然后，利用連鎖不平衡關(guān)系推測可能的疾病或性狀的易感基因或區(qū)域，從而尋找與疾病發(fā)生相關(guān)的致病位點。隨著人類基因組計劃和基于SNP的國際人類單體型圖譜(HapMap)構(gòu)建完成，GWAS得以實現(xiàn)并被廣泛應(yīng)運于糖尿病、精神分裂癥和哮喘等疾病[7,8]。經(jīng)典的GWAS通過建立全基因組高頻遺傳變異與表型的關(guān)聯(lián)，進(jìn)行多階段設(shè)計的病例對照研究，并將多個研究結(jié)果合并驗證。GWAS中<5.0′10–8的SNP位點才被認(rèn)為具有全基因組水平陽性。從2005年首次發(fā)表年齡相關(guān)性視網(wǎng)膜黃斑變性的GWAS以來，至今已經(jīng)發(fā)表數(shù)千項常見復(fù)雜性疾病或性狀的研究。2007年來，肺功能和COPD相關(guān)GWAS研究層出不窮，特別是COPD遺傳流行病學(xué)(COPD genetic epidemiology, COPDGene)和英國生物標(biāo)本庫(UK Biobank)等大樣本研究，極大地推動了COPD發(fā)病機制和尋找有效藥物靶點的研究。利用GWAS手段探討呼吸系統(tǒng)疾病，特別是鑒定COPD的潛在致病基因非常重要：(1)可以更加全面地了解疾病發(fā)展和呼吸道正常病理生理功能；(2)有利于根據(jù)確定的藥物靶標(biāo)研發(fā)新的治療策略；(3)通過確定一系列風(fēng)險性和安全性遺傳變異，可改善風(fēng)險評估預(yù)防疾病，或者做出更早、更準(zhǔn)確的診斷；(4)利用遺傳信息將疾病分為不同表型或亞型；(5)利用遺傳信息數(shù)據(jù)，使患者藥物治療獲益更多、副作用更少，推動藥物遺傳學(xué)發(fā)展[9]。截至2019年11月21日，通過查詢NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)網(wǎng)站發(fā)現(xiàn)，共有4200余篇文章涉及COPD，有近40項肺功能或COPD的GWAS隊列研究，發(fā)現(xiàn)大量SNPs與肺功能或COPD相關(guān)(圖1，圖2)。本文將從GWAS與肺功能、GWAS與COPD及COPD亞型的關(guān)系進(jìn)行闡述，并介紹基于GWAS的COPD藥物研發(fā)，以期為COPD基因和基因組學(xué)研究提供參考。

1 GWAS與肺功能

肺功能檢測是診斷COPD的必備條件。據(jù)報道，COPD與FEV1和FVC的遺傳相關(guān)性分別為?0.76和?0.9[10]；在歐洲和美國的雙胞胎研究中發(fā)現(xiàn)，F(xiàn)EV1的遺傳力估計達(dá)0.77[11]。隨著研究的深入，發(fā)現(xiàn)肺功能和COPD兩者均具有相關(guān)性的易感基因位點。Hall等[12]通過文獻(xiàn)復(fù)習(xí)發(fā)現(xiàn)28個易感基因位點同時與肺功能和COPD相關(guān)(表1)。Wain等[13]分析發(fā)現(xiàn)在97個與肺功能相關(guān)的致病基因中，95個與COPD有關(guān)。這些重疊的遺傳變異/致病基因進(jìn)一步確認(rèn)了基因座與疾病的相關(guān)性，并預(yù)計其可能發(fā)揮重要的病理生理功能。因此，基于肺功能的GWAS可發(fā)現(xiàn)更多致病基因，對于揭示COPD發(fā)病機制具有很好的科學(xué)意義。

Wilk等[14]于2007年在美國雷明漢心臟研究中心開展了第1項肺功能GWAS研究，該研究涉及10項肺功能測量(表2)和70,987個常染色體SNP，提示和是與肺功能相關(guān)的基因。2009年，他和同事又在7691名參與者中研究表型FEV1/FVC，發(fā)現(xiàn)在4q31區(qū)域上有4個SNP與FEV1/FVC相關(guān)，其中SNP rs13147758還與家系的FEV1/FVC顯著相關(guān)；這些SNPs均與基因靠近[15]。由此，他們認(rèn)為4號染色體區(qū)域具有影響肺功能的遺傳效應(yīng)，值得進(jìn)一步研究。

圖1 與肺功能(Pulmonary function measurement)相關(guān)SNPs分布圖

以關(guān)鍵詞“pulmonary function measurement”使用NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)查詢獲得相關(guān)研究109項、相關(guān)SNPs 6306個。其中rs6828540(位于Chr.4:144542079，定位基因AC098588.1、AC098588.2)的值最顯著。數(shù)據(jù)查詢截至2020年6月4日。

圖2 與COPD相關(guān)的SNPs點狀分布圖

以關(guān)鍵詞“chronic obstructive pulmonary disease”使用NHGS-GWAS catalog (https://www.ebi.ac.uk/gwas/)查詢，共獲得相關(guān)研究51項、相關(guān)SNPs 1076個。其中rs13140176(位于Chr.4:144567946，風(fēng)險等位基因A，定位基因AC098588.1、AC098588.2)的值最顯著。數(shù)據(jù)查詢截至2020年6月4日。

隨著meta分析的應(yīng)用，更多與肺功能相關(guān)變異位點被確定。2010年，Hancock等[16]對4個組群(Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Rotterdam Study (RS)) (Cohorts for Heart and Aging Research in Genomic Epidemiology consortium study, CHARGE研究)的20,890名歐洲后裔meta分析，明確8個與FEV1/FVC相關(guān)的基因變異位點(、、、、、、和)及1個與FEV1相關(guān)的基因位點()。同年，Repapi等[17]對SpiroMeta、CHARGE等研究涉及的74,564名歐洲后裔進(jìn)行meta分析，明確了5個新的肺功能(FEV1、FEV1/FVC)相關(guān)常見變異(com-mon variant)，分別為2q35()、4q24()、5q33 ()、6p21()和15q23()；并在人類肺組織中驗證、、、和的mRNA表達(dá)。2012年，Hancock等[18]通過meta分析，確定了2個(和)與FEV1/FVC相關(guān)、1個()與FEV1相關(guān)的新基因座，另外位于、、和、的SNPs與FEV1/FVC或FEV1相關(guān)。2014年，Loth等[19]發(fā)現(xiàn)6個與肺功能FVC相關(guān)的SNPs，并定位于、、、、和；同時，在基于多民族動脈粥樣硬化研究(multi-ethnic study of atherosclerosis，MESA)的563名中國裔中未發(fā)現(xiàn)有與中國裔肺功能相關(guān)的SNPs。

表1 肺功能與COPD重疊致病基因

表2 首項肺功能全基因組關(guān)聯(lián)研究采用的測量指標(biāo)

上述指標(biāo)是2007年由Wilk等[14]首次采用，用于評估肺功能測量指標(biāo)與相關(guān)變異位點的相關(guān)性。

隨著世界最大隊列樣本庫(UK Biobank)的應(yīng)用，肺功能GWAS研究獲得了更多的成果。2017年，Wain等[13]基于UK BiLEVEL的48,943名參與者和第二階段基于95,375名來自UK Biobank、SpiroMeta和英國家庭縱向研究(UK household longitudinal study, UKHLS)的參與者，發(fā)現(xiàn)與肺功能(FEV1、FVC或FEV1/FVC)相關(guān)的遺傳變異位點從54個增加至97個，其中新發(fā)現(xiàn)43個；經(jīng)富集分析發(fā)現(xiàn)該97個遺傳變異位點均與發(fā)育、彈性纖維和表觀遺傳學(xué)調(diào)節(jié)通路相關(guān)。因此，隨著GWAS研究的深入和生物信息學(xué)的應(yīng)用，將會進(jìn)一步揭示致病基因的生物學(xué)功能。

2019年，Shrine等[20]發(fā)表了迄今為止樣本量最大、相關(guān)位點最多的研究，他們發(fā)現(xiàn)有257個位點與肺功能(FEV1、FVC、FEV1/FVC和PEF)相關(guān)，其中新發(fā)現(xiàn)位點139個，共確認(rèn)107個參與基因表達(dá)、蛋白表達(dá)和功能注釋的致病基因(causal gene) (表3)，8個同時與有害變異(deleterious variant)和表達(dá)數(shù)量性狀基因座(expression quantitative trait locus, eQTL)有關(guān)，1個同時與eQTL和蛋白質(zhì)數(shù)量性狀基因座(protein quantitative trait locus, pQTL)有關(guān)，1個同時與有害變異和pQTL有關(guān)，13個僅與有害變異有關(guān)，81個與eQTL及3個與pQTL關(guān)聯(lián)。該研究首次利用GWAS發(fā)現(xiàn)與最大呼氣流量(peak expi-ratory flow，PEF)關(guān)聯(lián)的致病基因，其中有133個位點與PEF相關(guān)(<10E-5)，如已經(jīng)明確與囊性纖維化相關(guān)，同時在UK Biobank中發(fā)現(xiàn)與PEF高度相關(guān)。將致病基因富集分析，發(fā)現(xiàn)有部分致病基因參與纖毛生成(ciliogenesis，包括KIAA0753、CDK2和CEP72)過程，提示纖毛功能的損傷與COPD的發(fā)生發(fā)展密切相關(guān)。因此，肺功能的GWAS研究，不僅局限于肺功能的表型研究，同時可揭示COPD的發(fā)病機制和病理生理過程，為后續(xù)單基因或多基因的基礎(chǔ)提供理論基礎(chǔ)。

2 GWAS與COPD

雖然肺功能作為檢測COPD氣流受限的必備手段，但肺功能相關(guān)的遺傳變異/致病基因與疾病(COPD)是否相關(guān)，仍受到人們的質(zhì)疑。因此，需要對遺傳變異與COPD相關(guān)性展開GWAS研究。

2009年，Pillai等[32]首次開展COPD的GWAS研究：通過823名COPD患者和810名吸煙者的隊列研究，選取前100個SNPs在NETT和NAS研究中驗證，發(fā)現(xiàn)2個SNPs(rs8034191和rs1051730)位于位點；同時雖未達(dá)到基因組關(guān)聯(lián)統(tǒng)計學(xué)意義，但也與FEV1/FVC相關(guān)；因此，提示和均存在COPD的重要風(fēng)險位點。2010年，Cho等[33]通過2940名COPD和1380名對照組(兩組均為既往或正在吸煙者)，確認(rèn)rs7671167和rs1903003位于1個新的致病基因(4q22.1)位點。此后陸續(xù)有較多COPD的GWAS研究報道，如Van Durme等[34]基于著名的鹿特丹研究，發(fā)現(xiàn)了與COPD風(fēng)險相關(guān)；Brehm等[35]研究表明2個SNPs位于，SNP的不同可能與表達(dá)有關(guān)，肺組織中表達(dá)升高與肺功能惡化有關(guān)；Castaldi等[23]研究發(fā)現(xiàn)32個SNPs位于/靠近17個致病基因，其中11個為既往4項GWAS研究(NETT/NAS、挪威病例對照研究、ECLIPSE、COPDGene)已報道。2012年，Cho等[36]基于4項研究(ECLIPSE、NAS和NETT、GenKOLS、COPDGene)發(fā)現(xiàn)了一個位于19q13的新基因座，rs7937和rs2604894與嚴(yán)重COPD相關(guān)。2012~2017年間，Wilk等[28]、Hanse等l[37]、Cho等[24]、Dijkstra等[26]、Hardin等[38]及其他研究者[31,39~43]又先后發(fā)表了多篇GWAS在COPD中的研究，先后發(fā)現(xiàn)、、、和等易感基因與COPD相關(guān)。2017年，Hobbs等[10]發(fā)現(xiàn)22個與COPD相關(guān)的基因座，其中新發(fā)現(xiàn)13個基因座(同時包含9個與肺功能相關(guān))，但未發(fā)現(xiàn)與哮喘存在基因座重疊。最新研究表明在6p21-22區(qū)域、、、和存在COPD與哮喘的共享片段，除外，其余基因座作用方向一致[21]。因此，隨著GWAS研究的深入和樣本量的增多，COPD相關(guān)的致病基因或基因座研究不斷取得新進(jìn)展

表3 107個參與基因表達(dá)、蛋白表達(dá)和功能注釋的致病基因

隨后，科學(xué)家們又發(fā)現(xiàn)了更多的致病基因。Wain等[13]發(fā)現(xiàn)的97個致病基因中，51個與COPD定義相關(guān)，30個與COPD易感性相關(guān)(<5.26′10–4)，但未發(fā)現(xiàn)有遺傳變異或遺傳危險系數(shù)與COPD急性發(fā)作相關(guān)。他們還研究了來自中國慢性病前瞻研究項目協(xié)作組(China Kadoorie Biobank cohort, CKB)的7116例COPD (20,919例對照)和5292例急性加重病例(1824 對照組)的71個遺傳變異，發(fā)現(xiàn)有39個致病基因在歐洲人和中國人樣本中作用方向一致，其中7個達(dá)到統(tǒng)計學(xué)意義(<0.05) (表4)，說明在歐洲人群與中國人群中，某些遺傳因素對COPD具有共同的效應(yīng)，但仍需進(jìn)一步的實驗證明。

2019年，Sakornsakolpat等[21]匯總25項GWAS的35,735例COPD和222,076例對照組，發(fā)現(xiàn)82個與肺功能或COPD相關(guān)的基因座，其中原有47個、新發(fā)現(xiàn)35個；發(fā)現(xiàn)156個致病基因位于該82個基因座中，為闡述COPD疾病易感性和臨床異質(zhì)性提供新的視角。35個新基因座中，有9個與Shine等[20]報道相同。包括該82個基因座在內(nèi)，使用10%的COPD患病率解釋了7.0%表型變異(phenotypic variant)，與最近的22個基因座所解釋的4.7%相比[10]，所解釋的COPD表型變異增加了48%，可能存在一定的效應(yīng)高估。通過富集分析發(fā)現(xiàn)165個基因集的FDR<5%，其中44%與發(fā)育過程相關(guān)，如肺發(fā)育、肺泡發(fā)育和肺形態(tài)發(fā)生等；還有細(xì)胞外基質(zhì)相關(guān)途徑，及Wnt、SMAD、MAPK等信號通路[21]。因此，進(jìn)一步支持早期生活事件在COPD患病風(fēng)險中的關(guān)鍵作用，COPD患病風(fēng)險的很大一部分可能在生命的早期即已決定，遺傳變異可能會決定初始的肺功能和肺生長模式。

目前已進(jìn)入后GWAS時代，如何實現(xiàn)GWAS成果轉(zhuǎn)化是當(dāng)前的研究熱點。Zhou等[44]使用shRNA干擾表達(dá)，發(fā)現(xiàn)參與細(xì)胞外基質(zhì)和細(xì)胞增殖等過程。COPD易感基因在人類氣道和肺臟中均有表達(dá)，通過使用基因敲除(Fam13a)小鼠和在人類肺組織中驗證，其可通過抑制β-catenin信號通路促進(jìn)肺氣腫形成[45]；另外還在香煙誘導(dǎo)小鼠模型中發(fā)現(xiàn)可促進(jìn)脂肪酸- β氧化(fatty acid β-oxidation, FAO)過程[46]。本課題組也先后進(jìn)一步闡明了[47~49]、[50]和[51]等易感基因的表達(dá)和病理生理功能。通過單個基因或多個基因的細(xì)胞模型和/或動物模型試驗，為揭示COPD潛在發(fā)病機制提供了全新的思路。

3 GWAS與COPD亞型

雖然肺功能是診斷COPD的金標(biāo)準(zhǔn)，然而依賴肺功能檢測指標(biāo)診斷COPD存在明顯缺陷，因為COPD的發(fā)病機制存在不同的遺傳和環(huán)境因素，包含不同的病理生理學(xué)機制，因此只有研究基于不同遺傳背景、環(huán)境因素的病理生理相關(guān)的亞型才更具有意義。

表4 歐洲人群與中國人群7個作用方向一致的變異位點

*<0.05。

COPD精準(zhǔn)治療需要兼顧亞型和表型，根據(jù)分子標(biāo)志物實現(xiàn)不同亞型的鑒別，實現(xiàn)分層醫(yī)學(xué)(stra-tified medicine)，真正實現(xiàn)個體化和個性化治療。

4 基于GWAS的COPD藥物研發(fā)

實現(xiàn)GWAS成果轉(zhuǎn)化可能需要幾年甚至十幾年的時間，但是基于GWAS靶標(biāo)設(shè)計藥物可事半功倍，加速藥物研發(fā)。目前，共114種臨床試驗或批準(zhǔn)的藥物涉及COPD，160個靶標(biāo)正在開展研究(截至2019年12月15日，https://www.targetvalidation.org/)。比如，由編碼的毒蕈堿型乙酰膽堿受體M3是明確的藥物靶標(biāo)，針對該藥物靶標(biāo)已有許多批準(zhǔn)的藥物，包括用于治療哮喘和慢性阻塞性肺疾病的藥物[13]。編碼5-羥色胺受體的在早期的肺功能GWAS中就已被發(fā)現(xiàn)。與FVC(和FEV1)相關(guān)，編碼肌醇多磷酸5磷酸酶E，另一成分磷酸肌醇3激酶(PI3K)δ是正在開發(fā)中的COPD和哮喘的藥物靶標(biāo)[13]。

肺組織中的表達(dá)減少和COPD風(fēng)險降低有關(guān)，因此，抑制表達(dá)可能具有保護(hù)性作用。Hedgedog信號通路在肺臟早期發(fā)育中發(fā)揮重要的作用，其中、和作為該信號通路分子，它們是肺功能相關(guān)聯(lián)的潛在致病基因[61]。另外，據(jù)報道新發(fā)現(xiàn)有7個與COPD和肺功能相關(guān)的可治療靶標(biāo)，包括、、、、、和[21]；目前許多靶標(biāo)僅依賴于細(xì)胞模型的初步探索，但其在細(xì)胞內(nèi)或體內(nèi)的相互作用和效果仍需進(jìn)一步通過開展臨床試驗評估。隨著后GWAS時代轉(zhuǎn)化研究的深入，必將發(fā)現(xiàn)更多的藥物靶標(biāo)及開發(fā)新型高效藥物提供基礎(chǔ)。

5 結(jié)語與展望

盡管在COPD中成功地開展了全基因組關(guān)聯(lián)研究，但仍存在如下挑戰(zhàn)：(1) GWAS通過病例對照尋找差異SNPs，但大部分SNPs位于非編碼區(qū)，僅有一部分基因變異與疾病表型相關(guān)。(2)通過GWAS識別的遺傳變異僅占遺傳力的一小部分，已知肺功能信號分別占FEV1、FVC和FEV1 / FVC的遺傳力的9.6%、6.4%和14.3%[13]。因此，GWAS僅識別常見變異，而忽略了罕見變異、基因拷貝數(shù)量變異等其他類型變異。(3)當(dāng)前商業(yè)化的SNPs芯片多基于高加索人群設(shè)計，亟需設(shè)計基于亞洲人群遺傳多態(tài)性的芯片。(4)基于肺功能診斷的COPD，受多種因素的影響，如對樣本量、資料收集的完整性、研究對象的選擇及診斷方法等。(5)在COPD研究中，大多數(shù)研究均聚焦于肺通氣功能測量，而非COPD本身，使得在疾病中的應(yīng)用和轉(zhuǎn)化面臨困難。(6)無法完全匹配病例組與對照組參與者，而且COPD患者可能存在多種并發(fā)癥，如心血管疾病、2型糖尿病等其他疾病。

在歐美等國家，開展了大規(guī)模的COPD基因和基因組學(xué)研究，但目前國內(nèi)COPD基因組學(xué)研究嚴(yán)重落后，尚無一項特定的針對COPD開展大規(guī)模GWAS研究[62]。因此，應(yīng)該抓住機遇，加強國際合作，建立以中國漢族人群為基礎(chǔ)的慢性阻塞性肺疾病全基因組關(guān)聯(lián)研究，利用先進(jìn)的分子生物學(xué)技術(shù)，闡明中國人COPD的發(fā)病機制、尋找有效治療靶點、發(fā)現(xiàn)新型生物標(biāo)志物和改善COPD和亞型的預(yù)測。推進(jìn)個性化預(yù)防和治療COPD，降低我國COPD患病率和死亡率，全面提高全民健康水平。

[1] GOLD. The Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, manage-ment, and prevention of chronic obstructive pulmonary disease (Updated 2019). 2019, http://goldcopd.org.

[2] Wang C, Xu JY, Yang L, Xu YJ, Zhang XY, Bai CX, Kang J, Ran PX, Shen HH, Wen FQ, Huang KW, Yao WZ, Sun TY, Shan GL, Yang T, Lin YX, Wu SN, Zhu JG, Wang RY, Shi ZH, Zhao JP, Ye XW, Song YL, Wang QY, Zhou YM, Ding LR, Yang T, Chen YH, Guo YF, Xiao F, Lu Y, Peng XX, Zhang B, Xiao D, Chen CS, Wang ZM, Zhang H, Bu XN, Zhang XL, An L, Zhang S, Cao ZX, Zhan QY, Yang YH, Cao B, Dai HP, Liang LR, He J. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study., 2018, 391(10131): 1706– 1717.

[3] Collaborators GCRD. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015., 2017, 5(9): 691–706.

[4] Kheirallah AK, Miller S, Hall IP, Sayers I. Translating lung function genome-wide association study (GWAS) findings: new insights for lung biology., 2016, 93: 57–145.

[5] Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Artigas MS, Billington CK, Kheirallah AK, Allen R, Cook JP, Probert K, Obeidat Me, Bossé Y, Hao K, Postma DS, Paré PD, Ramasamy A, M?gi R, Mihailov E, Reinmaa E, Melén E, O'Connell J, Frangou E, Delaneau O, Freeman C, Petkova D, McCarthy M, Sayers I, Deloukas P, Hubbard R, Pavord I, Hansell AL, Thomson NC, Zeggini E, Morris AP, Marchini J, Strachan DP, Tobin MD, Hall IP. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank., 2015, 3(10): 769–781.

[6] Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers., 2009, 374(9691): 733–743.

[7] Liang WQ, Hou Y, Zhao CY. Schizophrenia-associated single nucleotide polymorphisms affecting microRNA function., 2019, 41(8): 677–685.梁文權(quán), 侯豫, 趙存友. 精神分裂癥相關(guān)單核苷酸多態(tài)性調(diào)控microRNA功能研究進(jìn)展. 遺傳, 2019, 41(8): 677–685.

[8] Wang YY, Wang ZX, Hu YD, Wang L, Li N, Zhang B, Han W, Jiang JM. Current status of pathway analysis in genome-wide association study., 2017, 39(8): 707–716.王鈺嫣, 王子興, 胡耀達(dá), 王蕾, 李寧, 張彪, 韓偉, 姜晶梅. 全基因組關(guān)聯(lián)研究通路分析方法現(xiàn)狀. 遺傳, 2017, 39(8): 707–716.

[9] Obeidat M, Hall IP. Genetics of complex respiratory diseases: implications for pathophysiology and pharma-cology studies., 2011, 163(1): 96–105.

[10] Hobbs BD, de Jong K, Lamontagne M, Bosse Y, Shrine N, Artigas MS, Wain LV, Hall IP, Jackson VE, Wyss AB, London SJ, North KE, Franceschini N, Strachan DP, Beaty TH, Hokanson JE, Crapo JD, Castaldi PJ, Chase RP, Bartz TM, Heckbert SR, Psaty BM, Gharib SA, Zanen P, Lammers JW, Oudkerk M, Groen HJ, Locantore N, Tal-Singer R, Rennard SI, Vestbo J, Timens W, Pare PD, Latourelle JC, Dupuis J, O'Connor GT, Wilk JB, Kim WJ, Lee MK, Oh YM, Vonk JM, de Koning HJ, Leng S, Belinsky SA, Tesfaigzi Y, Manichaikul A, Wang XQ, Rich SS, Barr RG, Sparrow D, Litonjua AA, Bakke P, Gulsvik A, Lahousse L, Brusselle GG, Stricker BH, Uitterlinden AG, Ampleford EJ, Bleecker ER, Woodruff PG, Meyers DA, Qiao D, Lomas DA, Yim JJ, Kim DK, Hawrylkiewicz I, Sliwinski P, Hardin M, Fingerlin TE, Schwartz DA, Postma DS, MacNee W, Tobin MD, Silverman EK, Boezen HM, Cho MH. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis., 2017, 49(3): 426–432.

[11] Hubert HB, Fabsitz RR, Feinleib M, Gwinn C. Genetic and environmental influences on pulmonary function in adult twins., 1982, 125(4): 409–415.

[12] Hall R, Hall IP, Sayers I. Genetic risk factors for the development of pulmonary disease identified by genome- wide association., 2019, 24(3): 204–214.

[13] Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, Obeidat M, Henry AP, Portelli MA, Hall RJ, Billington CK, Rimington TL, Fenech AG, John C, Blake T, Jackson VE, Allen RJ, Prins BP, Campbell A, Porteous DJ, Jarvelin MR, Wielscher M, James AL, Hui J, Wareham NJ, Zhao JH, Wilson JF, Joshi PK, Stubbe B, Rawal R, Schulz H, Imboden M, Probst-Hensch NM, Karrasch S, Gieger C, Deary IJ, Harris SE, Marten J, Rudan I, Enroth S, Gyllensten U, Kerr SM, Polasek O, Kahonen M, Surakka I, Vitart V, Hayward C, Lehtimaki T, Raitakari OT, Evans DM, Henderson AJ, Pennell CE, Wang CA, Sly PD, Wan ES, Busch R, Hobbs BD, Litonjua AA, Sparrow DW, Gulsvik A, Bakke PS, Crapo JD, Beaty TH, Hansel NN, Mathias RA, Ruczinski I, Barnes KC, Bosse Y, Joubert P, van den Berge M, Brandsma CA, Pare PD, Sin DD, Nickle DC, Hao K, Gottesman O, Dewey FE, Bruse SE, Carey DJ, Kirchner HL, Jonsson S, Thorleifsson G, Jonsdottir I, Gislason T, Stefansson K, Schurmann C, Nadkarni G, Bottinger EP, Loos RJ, Walters RG, Chen Z, Millwood IY, Vaucher J, Kurmi OP, Li L, Hansell AL, Brightling C, Zeggini E, Cho MH, Silverman EK, Sayers I, Trynka G, Morris AP, Strachan DP, Hall IP, Tobin MD. Genome-wide association analyses for lung function and chronic obs-tructive pulmonary disease identify new loci and potential druggable targets., 2017, 49(3): 416–425.

[14] Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT. Framingham Heart Study genome-wide association: results for pulmonary function measures., 2007, 8(1): S8.

[15] Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, Myers RH, Borecki IB, Silverman EK, Weiss ST, O'Connor GT. A genome-wide association study of pulmonary function measures in the Framingham Heart Study., 2009, 5(3): e1000429.

[16] Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BHC, O'Connor GT, London SJ. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function., 2010, 42(1): 45–52.

[17] Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Wellcome Trust Case Control C, Barroso I, Loos RJ, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Peltonen L, Gyllensten U, Johansson A, Zaboli G, Campbell H, Wild SH, Wilson JF, Glaser S, Homuth G, Volzke H, Mangino M, Soranzo N, Spector TD, Polasek O, Rudan I, Wright AF, Heliovaara M, Ripatti S, Pouta A, Naluai AT, Olin AC, Toren K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Schnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Team NRS, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kahonen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, Tobin MD. Genome-wide association study identifies five loci associated with lung function., 2010, 42(1): 36–44.

[18] Hancock DB, Soler Artigas M, Gharib SA, Henry A, Manichaikul A, Ramasamy A, Loth DW, Imboden M, Koch B, McArdle WL, Smith AV, Smolonska J, Sood A, Tang W, Wilk JB, Zhai G, Zhao JH, Aschard H, Burkart KM, Curjuric I, Eijgelsheim M, Elliott P, Gu XJ, Harris TB, Janson C, Homuth G, Hysi PG, Liu JZ, Loehr LR, Lohman K, Loos RJ, Manning AK, Marciante KD, Obeidat M, Postma DS, Aldrich MC, Brusselle GG, Chen TH, Eiriksdottir G, Franceschini N, Heinrich J, Rotter JI, Wijmenga C, Williams OD, Bentley AR, Hofman A, Laurie CC, Lumley T, Morrison AC, Joubert BR, Rivadeneira F, Couper DJ, Kritchevsky SB, Liu YM, Wjst M, Wain LV, Vonk JM, Uitterlinden AG, Rochat T, Rich SS, Psaty BM, O'Connor GT, North KE, Mirel DB, Meibohm B, Launer LJ, Khaw KT, Hartikainen AL, Hammond CJ, Glaser S, Marchini J, Kraft P, Wareham NJ, Volzke H, Stricker BH, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin MR, Heckbert SR, Gudnason V, Boezen HM, Barr RG, Cassano PA, Strachan DP, Fornage M, Hall IP, Dupuis J, Tobin MD, London SJ. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function., 2012, 8(12): e1003098.

[19] Loth DW, Soler Artigas M, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, Lee MK, Strachan DP, James AL, Huffman JE, Vitart V, Ramasamy A, Wareham NJ, Kaprio J, Wang XQ, Trochet H, Kahonen M, Flexeder C, Albrecht E, Lopez LM, de Jong K, Thyagarajan B, Alves AC, Enroth S, Omenaas E, Joshi PK, Fall T, Vinuela A, Launer LJ, Loehr LR, Fornage M, Li G, Wilk JB, Tang WB, Manichaikul A, Lahousse L, Harris TB, North KE, Rudnicka AR, Hui J, Gu X, Lumley T, Wright AF, Hastie ND, Campbell S, Kumar R, Pin I, Scott RA, Pietilainen KH, Surakka I, Liu YM, Holliday EG, Schulz H, Heinrich J, Davies G, Vonk JM, Wojczynski M, Pouta A, Johansson A, Wild SH, Ingelsson E, Rivadeneira F, Volzke H, Hysi PG, Eiriksdottir G, Morrison AC, Rotter JI, Gao W, Postma DS, White WB, Rich SS, Hofman A, Aspelund T, Couper D, Smith LJ, Psaty BM, Lohman K, Burchard EG, Uitterlinden AG, Garcia M, Joubert BR, McArdle WL, Musk AB, Hansel N, Heckbert SR, Zgaga L, van Meurs JB, Navarro P, Rudan I, Oh YM, Redline S, Jarvis DL, Zhao JH, Rantanen T, O'Connor GT, Ripatti S, Scott RJ, Karrasch S, Grallert H, Gaddis NC, Starr JM, Wijmenga C, Minster RL, Lederer DJ, Pekkanen J, Gyllensten U, Campbell H, Morris AP, Gl?ser S, Hammond CJ, Burkart KM, Beilby J, Kritchevsky SB, Gudnason V, Hancock DB, Williams OD, Polasek O, Zemunik T, Kolcic I, Petrini MF, Wjst M, Kim WJ, Porteous DJ, Scotland G, Smith BH, Viljanen A, Heli?vaara M, Attia JR, Sayers I, Hampel R, Gieger C, Deary IJ, Boezen HM, Newman A, Jarvelin MR, Wilson JF, Lind L, Stricker BH, Teumer A, Spector TD, Melen E, Peters MJ, Lange LA, Barr RG, Bracke KR, Verhamme FM, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, London SJ. Genome-wide association analysis identifies six new loci associated with forced vital capacity., 2014, 46(7): 669–677.

[20] Shrine N, Guyatt AL, Erzurumluoglu AM, Jackson VE, Hobbs BD, Melbourne CA, Batini C, Fawcett KA, Song K, Sakornsakolpat P, Li XN, Boxall R, Reeve NF, Obeidat M, Zhao JH, Wielscher M, Weiss S, Kentistou KA, Cook JP, Sun BB, Zhou J, Hui J, Karrasch S, Imboden M, Harris SE, Marten J, Enroth S, Kerr SM, Surakka I, Vitart V, Lehtim?ki T, Allen RJ, Bakke PS, Beaty TH, Bleecker ER, Bossé Y, Brandsma CA, Chen ZM, Crapo JD, Danesh J, DeMeo DL, Dudbridge F, Ewert R, Gieger C, Gulsvik A, Hansell AL, Hao K, Hoffman JD, Hokanson JE, Homuth G, Joshi PK, Joubert P, Langenberg C, Li X, Li LM, Lin K, Lind L, Locantore N, Luan JA, Mahajan A, Maranville JC, Murray A, Nickle DC, Packer R, Parker MM, Paynton ML, Porteous DJ, Prokopenko D, Qiao DD, Rawal R, Runz H, Sayers I, Sin DD, Smith BH, Artigas MS, Sparrow D, Tal-Singer R, Timmers PRHJ, Van den Berge M, Whittaker JC, Woodruff PG, Yerges-Armstrong LM, Troyanskaya OG, Raitakari OT, K?h?nen M, Pola?ek O, Gyllensten U, Rudan I, Deary IJ, Probst-Hensch NM, Schulz H, James AL, Wilson JF, Stubbe B, Zeggini E, Jarvelin MR, Wareham N, Silverman EK, Hayward C, Morris AP, Butterworth AS, Scott RA, Walters RG, Meyers DA, Cho MH, Strachan DP, Hall IP, Tobin MD, Wain LV. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries., 2019, 51(3): 481–493.

[21] Sakornsakolpat P, Prokopenko D, Lamontagne M, Reeve NF, Guyatt AL, Jackson VE, Shrine N, Qiao DD, Bartz TM, Kim DK, Lee MK, Latourelle JC, Li XN, Morrow JD, Obeidat M, Wyss AB, Bakke P, Barr RG, Beaty TH, Belinsky SA, Brusselle GG, Crapo JD, de Jong K, DeMeo DL, Fingerlin TE, Gharib SA, Gulsvik A, Hall IP, Hokanson JE, Kim WJ, Lomas DA, London SJ, Meyers DA, O'Connor GT, Rennard SI, Schwartz DA, Sliwinski P, Sparrow D, Strachan DP, Tal-Singer R, Tesfaigzi Y, Vestbo J, Vonk JM, Yim JJ, Zhou X, Bosse Y, Manichaikul A, Lahousse L, Silverman EK, Boezen HM, Wain LV, Tobin MD, Hobbs BD, Cho MH. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations., 2019, 51(3): 494–505.

[22] Soler Artigas M, Wain LV, Repapi E, Obeidat M, Sayers I, Burton PR, Johnson T, Zhao JH, Albrecht E, Dominiczak AF, Kerr SM, Smith BH, Cadby G, Hui J, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Ebrahim S, Smith GD, Barroso I, Loos RJ, Wareham NJ, Cooper C, Dennison E, Shaheen SO, Liu JZ, Marchini J, Medical Research Council National Survey of H, Development Respiratory Study T, Dahgam S, Naluai AT, Olin AC, Karrasch S, Heinrich J, Schulz H, McKeever TM, Pavord ID, Heliovaara M, Ripatti S, Surakka I, Blakey JD, Kahonen M, Britton JR, Nyberg F, Holloway JW, Lawlor DA, Morris RW, James AL, Jackson CM, Hall IP, Tobin MD, SpiroMeta C. Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function., 2011, 184(7): 786–795.

[23] Castaldi PJ, Cho MH, Litonjua AA, Bakke P, Gulsvik A, Lomas DA, Anderson W, Beaty TH, Hokanson JE, Crapo JD, Laird N, Silverman EK. The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility., 2011, 45(6): 1147–1153.

[24] Cho MH, McDonald MLN, Zhou XB, Mattheisen M, Castaldi PJ, Hersh CP, DeMeo DL, Sylvia JS, Ziniti J, Laird NM, Lange C, Litonjua AA, Sparrow D, Casaburi R, Barr RG, Regan EA, Make BJ, Hokanson JE, Lutz S, Dudenkov TM, Farzadegan H, Hetmanski JB, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Crapo JD, Silverman EK, Beaty TH. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis., 2014, 2(3): 214–225.

[25] Lutz SM, Cho MH, Young K, Hersh CP, Castaldi PJ, McDonald ML, Regan E, Mattheisen M, DeMeo DL, Parker M, Foreman M, Make BJ, Jensen RL, Casaburi R, Lomas DA, Bhatt SP, Bakke P, Gulsvik A, Crapo JD, Beaty TH, Laird NM, Lange C, Hokanson JE, Silverman EK. A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry., 2015, 16: 138.

[26] Dijkstra AE, Boezen HM, Van Den Berge M, Vonk JM, Hiemstra PS, Barr RG, Burkart KM, Manichaikul A, Pottinger TD, Silverman EK, Cho MH, Crapo JD, Beaty TH, Bakke P, Gulsvik A, Lomas DA, Bossé Y, Nickle DC, Paré PD, de Koning HJ, Lammers JW, Zanen P, Smolonska J, Wijmenga C, Brandsma CA, Groen HJM, Postma DS. Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD., 2015, 45(1): 60–75.

[27] Soler Artigas M, Wain LV, Miller S, Kheirallah AK, Huffman JE, Ntalla I, Shrine N, Obeidat M, Trochet H, McArdle WL, Alves AC, Hui J, Zhao JH, Joshi PK, Teumer A, Albrecht E, Imboden M, Rawal R, Lopez LM, Marten J, Enroth S, Surakka I, Polasek O, Lyytikainen LP, Granell R, Hysi PG, Flexeder C, Mahajan A, Beilby J, Bosse Y, Brandsma CA, Campbell H, Gieger C, Glaser S, Gonzalez JR, Grallert H, Hammond CJ, Harris SE, Hartikainen AL, Heliovaara M, Henderson J, Hocking L, Horikoshi M, Hutri-Kahonen N, Ingelsson E, Johansson A, Kemp JP, Kolcic I, Kumar A, Lind L, Melen E, Musk AW, Navarro P, Nickle DC, Padmanabhan S, Raitakari OT, Ried JS, Ripatti S, Schulz H, Scott RA, Sin DD, Starr JM, BiLEVE UK, Vinuela A, Volzke H, Wild SH, Wright AF, Zemunik T, Jarvis DL, Spector TD, Evans DM, Lehtimaki T, Vitart V, Kahonen M, Gyllensten U, Rudan I, Deary IJ, Karrasch S, Probst-Hensch NM, Heinrich J, Stubbe B, Wilson JF, Wareham NJ, James AL, Morris AP, Jarvelin MR, Hayward C, Sayers I, Strachan DP, Hall IP, Tobin MD. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation., 2015, 6: 8658.

[28] Wilk JB, Shrine NR, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, Smith AV, Heckbert SR, Smolonska J, Tang W, Loth DW, Curjuric I, Hui J, Cho MH, Latourelle JC, Henry AP, Aldrich M, Bakke P, Beaty TH, Bentley AR, Borecki IB, Brusselle GG, Burkart KM, Chen TH, Couper D, Crapo JD, Davies G, Dupuis J, Franceschini N, Gulsvik A, Hancock DB, Harris TB, Hofman A, Imboden M, James AL, Khaw KT, Lahousse L, Launer LJ, Litonjua A, Liu Y, Lohman KK, Lomas DA, Lumley T, Marciante KD, McArdle WL, Meibohm B, Morrison AC, Musk AW, Myers RH, North KE, Postma DS, Psaty BM, Rich SS, Rivadeneira F, Rochat T, Rotter JI, Soler Artigas M, Starr JM, Uitterlinden AG, Wareham NJ, Wijmenga C, Zanen P, Province MA, Silverman EK, Deary IJ, Palmer LJ, Cassano PA, Gudnason V, Barr RG, Loos RJ, Strachan DP, London SJ, Boezen HM, Probst-Hensch N, Gharib SA, Hall IP, O'Connor GT, Tobin MD, Stricker BH. Genome wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction., 2012, 186(7): 622–632.

[29] Burkart KM, Sofer T, London SJ, Manichaikul A, Hartwig FP, Yan Q, Soler Artigas M, Avila L, Chen W, Davis Thomas S, Diaz AA. A Genome-wide association study in Hispanics/Latinos identifies novel signals for lung function. The hispanic community health Study/Study of latinos., 2018, 198(2): 208– 219.

[30] Jackson VE, Latourelle JC, Wain LV, Smith AV, Grove ML, Bartz TM, Obeidat M, Province MA, Gao W, Qaiser B, Porteous DJ, Cassano PA, Ahluwalia TS, Grarup N, Li J, Altmaier E, Marten J, Harris SE, Manichaikul A, Pottinger TD, Li-Gao R, Lind-Thomsen A, Mahajan A, Lahousse L, Imboden M, Teumer A, Prins B, Lyytik?inen LP, Eiriksdottir G, Franceschini N, Sitlani CM, Brody JA, Bossé YT, Timens W, Kraja A, Loukola A, Tang WB, Liu YM, Bork-Jensen J, Justesen JM, Linneberg A, Lange LA, Rawal R, Karrasch S, Huffman JE, Smith BH, Davies G, Burkart KM, Mychaleckyj JC, Bonten TN, Enroth S, Lind L, Brusselle GG, Kumar A, Stubbe B, K?h?nen M, Wyss AB, Psaty BM, Heckbert SR, Hao K, Rantanen T, Kritchevsky SB, Lohman K, Skaaby T, Pisinger C, Hansen T, Schulz H, Polasek O, Campbell A, Starr JM, Rich SS, Mook-Kanamori DO, Johansson ?, Ingelsson E, Uitterlinden A, Weiss S, Raitakari OT, Gudnason V, North KE, Gharib SA, Sin DD, Taylor KD, O'Connor GT, Kaprio J, Harris TB, Pederson O, Vestergaard H, Wilson JG, Strauch K, Hayward C, Kerr S, Deary IJ, Barr R, de Mutsert R, Gyllensten U, Morris AP, Ikram MA, Probst-Hensch N, Gl?ser S, Zeggini E, Lehtim?ki T, Strachan DP, Dupuis J, Morrison AC, Hall IP, Tobin MD, London SJ. Meta-analysis of exome array data identifies six novel genetic loci for lung function., 2018, 3: 4.

[31] Morrow JD, Qiu WL, Chhabra D, Rennard SI, Belloni P, Belousov A, Pillai SG, Hersh CP. Identifying a gene expression signature of frequent COPD exacerbations in peripheral blood using network methods., 2015, 8(1): 1.

[32] Pillai SG, Ge DL, Zhu GH, Kong XY, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, Ruppert A, L?drup Carlsen KC, Roses A, Anderson W, Rennard SI, Lomas DA, Silverman EK, Goldstein DB. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci., 2009, 5(3): e1000421.

[33] Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, DeMeo DL, Hunninghake GM, Litonjua AA, Sparrow D, Lange C, Won S, Murphy JR, Beaty T, Regan EA, Make BJ, Hokanson JE, Crapo JD, Kong XQ, Anderson WH, Tal-Singer RM, Lomas DA, Bakke P, Gulsvik A, Pillai SG, Silverman EK. Variants inare associated with chronic obstructive pulmonary disease., 2010, 42(3): 200–202.

[34] Van Durme YMTA, Eijgelsheim M, Joos GF, Hofman A, Uitterlinden AG, Brusselle GG, Stricker BHC. Hedgehog- interacting protein is a COPD susceptibility gene: the Rotterdam Study., 2010, 36(1): 89–95.

[35] Brehm JM, Hagiwara K, Tesfaigzi Y, Bruse S, Mariani TJ, Bhattacharya S, Boutaoui N, Ziniti JP, Soto-Quiros ME, Avila L, Cho MH, Himes B, Litonjua AA, Jacobson F, Bakke P, Gulsvik A, Anderson WH, Lomas DA, Forno E, Datta S, Silverman EK, Celedón JC. Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease., 2011, 66(12): 1085–1090.

[36] Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, Himes BE, Sylvia JS, Klanderman BJ, Ziniti JP, Lange C, Litonjua AA, Sparrow D, Regan EA, Make BJ, Hokanson JE, Murray T, Hetmanski JB, Pillai SG, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, Yates JC, Agusti A, Calverley PM, Celli B, Crim C, Rennard S, Wouters E, Bakke P, Gulsvik A, Crapo JD, Beaty TH, Silverman EK. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13., 2012, 21(4): 947–957.

[37] Hansel NN, Pare PD, Rafaels N, Sin DD, Sandford A, Daley D, Vergara C, Huang LL, Elliott WM, Pascoe CD, Arsenault BA, Postma DS, Boezen HM, Bossé Y, van den Berge M, Hiemstra PS, Cho MH, Litonjua AA, Sparrow D, Ober C, Wise RA, Connett J, Neptune ER, Beaty TH, Ruczinski I, Mathias RA, Barnes KC. Genome-wide association study identification of novel loci associated with airway responsiveness in chronic obstructive pulmo-nary disease., 2015, 53(2): 226–234.

[38] Hardin M, Cho M, McDonald ML, Beaty T, Ramsdell J, Bhatt S, Van Beek EJR, Make BJ, Crapo JD, Silverman EK, Hersh CP. The clinical and genetic features of COPD- asthma overlap syndrome., 2014, 44(2): 341–350.

[39] Lee JH, Cho MH, Hersh CP, McDonald MLN, Crapo JD, Bakke PS, Gulsvik A, Comellas AP, Wendt CH, Lomas DA, Kim V, Silverman EK. Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease., 2014, 15(1): 113.

[40] Chen W, Brehm JM, Manichaikul A, Cho MH, Boutaoui N, Yan Q, Burkart KM, Enright PL, Rotter JI, Petersen H, Leng HG, Obeidat M, Bossé Y, Brandsma CA, Hao K, Rich SS, Powell R, Avila L, Soto-Quiros M, Silverman EK, Tesfaigzi Y, Barr RG, Celedón JC. A Genome-Wide Association Study of chronic obstructive pulmonary disease in Hispanics., 2015, 12(3): 340–348.

[41] Hansel NN, Paré PD, Rafaels N, Sin DD, Sandford A, Daley D, Vergara C, Huang L, Elliott WM, Pascoe CD, Arsenault BA, Postma DS, Boezen HM, Bosse Y, van den Berge M, Hiemstra PS, Cho MH, Litonjua AA, Sparrow D, Ober C, Wise RA, Connett J, Neptune ER, Beaty TH, Ruczinski I, Mathias RA, Barnes KC. Genome-Wide Association Study identification of novel loci associated with airway responsiveness in chronic obstructive pul-monary disease., 2015, 53(2): 226–234.

[42] McDonald ML, Cho MH, Sorheim IC, Lutz SM, Castaldi PJ, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, Yates JC, Agusti A, Calverley PM, Celli B, Crim C, Rennard SI, Wouters EF, Bakke P, Tal-Singer R, Miller BE, Gulsvik A, Casaburi R, Wells JM, Regan EA, Make BJ, Hokanson JE, Lange C, Crapo JD, Beaty TH, Silverman EK, Hersh CP. Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease., 2014, 51(5): 678–687.

[43] Artigas MS, Wain LV, Shrine N, McKeever TM, BiLEVE U, Sayers I, Hall IP, Tobin MD. Targeted sequencing of lung function loci in chronic obstructive pulmonary disease cases and controls.e, 2017, 12(1): e0170222.

[44] Zhou XB, Qiu WL, Sathirapongsasuti JF, Cho MH, Mancini JD, Lao TT, Thibault DM, Litonjua AA, Bakke PS, Gulsvik A, Lomas DA, Beaty TH, Hersh CP, Anderson C, Geigenmuller U, Raby BA, Rennard SI, Perrella MA, Choi AMK, Quackenbush J, Silverman EK. Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells., 2013, 101(5): 263–272.

[45] Jiang ZQ, Lao TT, Qiu WL, Polverino F, Gupta K, Guo F, Mancini JD, Naing ZZC, Cho MH, Castaldi PJ, Sun Y, Yu J, Laucho-Contreras ME, Kobzik L, Raby BA, Choi AMK, Perrella MA, Owen CA, Silverman EK, Zhou XB. A chronic obstructive pulmonary disease susceptibility gene, FAM13A, regulates protein stability of β-catenin., 2016, 194(2): 185–197.

[46] Jiang ZQ, Knudsen NH, Wang G, Qiu WL, Naing ZZC, Bai Y, Ai XB, Lee CH, Zhou XB. Genetic control of fatty acid β-oxidation in chronic obstructive pulmonary disease., 2017, 56(6): 738–748.

[47] Obeidat M, Miller S, Probert K, Billington CK, Henry AP, Hodge E, Nelson CP, Stewart CE, Swan C, Wain LV, Artigas MS, Melén E, Ushey K, Hao K, Lamontagne M, Bossé Y, Postma DS, Tobin MD, Sayers I, Hall IP. GSTCD and INTS12 regulation and expression in the human lung., 2013, 8(9): e74630.

[48] Qian GQ, Yang NB, Shi JJ. Recent advances in nephronectin., 2019, 71(5): 799–805.

[49] Qian GQ, Henry A, Liu B, Miller S, Billington CK, Hall IP. Inhibition Of nephronectin expression In human bronchial epithelial cells using SiRNA knock-down. C71., 2016, A5866-A5866.

[50] Hodge E, Nelson CP, Miller S, Billington CK, Stewart CE, Swan C, Malarstig A, Henry AP, Gowland C, Melén E, Hall IP, Sayers I. HTR4 gene structure and altered expression in the developing lung., 2013, 14(1): 77.

[51] Miller S, Henry AP, Hodge E, Kheirallah AK, Billington CK, Rimington TL, Bhaker SK, Obeidat M, Melen E, Merid SK, Swan C, Gowland C, Nelson CP, Stewart CE, Bolton CE, Kilty I, Malarstig A, Parker SG, Moffatt MF, Wardlaw AJ, Hall IP, Sayers I. The Ser82 RAGE variant affects lung function and serum RAGE in smokers and sRAGE production., 2016, 11(10): e0164041.

[52] Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, MacNee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko GR, Wouters EFM, Martinez FJ. Chronic obstructive pulmonary disease phenotypes: the future of COPD., 2010, 182(5): 598–604.

[53] Thun GA, Imboden M, Ferrarotti I, Kumar A, Obeidat M, Zorzetto M, Haun M, Curjuric I, Couto Alves A, Jackson VE, Albrecht E, Ried JS, Teumer A, Lopez LM, Huffman JE, Enroth S, Bosse Y, Hao K, Timens W, Gyllensten U, Polasek O, Wilson JF, Rudan I, Hayward C, Sandford AJ, Deary IJ, Koch B, Reischl E, Schulz H, Hui J, James AL, Rochat T, Russi EW, Jarvelin MR, Strachan DP, Hall IP, Tobin MD, Dahl M, Fallgaard Nielsen S, Nordestgaard BG, Kronenberg F, Luisetti M, Probst-Hensch NM. Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels., 2013, 9(8): e1003585.

[54] Kong XY, Cho MH, Anderson W, Coxson HO, Muller N, Washko G, Hoffman EA, Bakke P, Gulsvik A, Lomas DA, Silverman EK, Pillai SG. Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema., 2011, 183(1): 43–49.

[55] Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JHN, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJM, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O’Connor GT, Boezen HM, Rich SS, Barr RG. Genome-wide study of percent emphysema on computed tomography in the general population. The multi-ethnic study of atherosclerosis lung/SNP health association resource Study., 2014, 189(4): 408–418.

[56] Cho MH, Castaldi PJ, Hersh CP, Hobbs BD, Barr RG, Tal-Singer R, Bakke P, Gulsvik A, San José Estépar R, Van Beek EJ, Coxson HO, Lynch DA, Washko GR, Laird NM, Crapo JD, Beaty TH, Silverma EK. A genome-wide association study of emphysema and airway quantitative imaging phenotypes., 2015, 192(5): 559–569.

[57] Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Benn M, Nielsen SF, Dahl M, Monique Verschuren W, Picavet HSJ, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bossé Y, Obeidat MA, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH, Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJM, Timens W, Marike Boezen H, Postma DS. Susceptibility to chronic mucus hypersecre-tion, a genome wide association study., 2014, 9(4): e91621.

[58] McDonald MN, Won S, Mattheisen M, Castaldi PJ, Cho MH, Rutten E, Hardin M, Yip WK, Rennard SI, Lomas DA, Wouters EFM, Agusti A, Casaburi R, Lange CP, O'Connor G, Hersh CP, Silverman EK. Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1., 2017, 8(3): 428–436.

[59] Lee JH, Cho MH, Hersh CP, McDonald ML, Wells JM, Dransfield MT, Bowler RP, Lynch DA, Lomas DA, Crapo JD, Silverman EK. IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease., 2015, 52(3): 365–376.

[60] Shi JJ, Qian GQ, Yin FY, Li GX. Research progress in risk factors in female patients with chronic obstructive pulmonary disease., 2018, 32(6): 1333–1336.石潔君, 錢國清, 尹鳳英, 李國祥. 女性慢性阻塞性肺疾病患者致病危險因素的研究進(jìn)展. 臨床與病理雜志, 2018, 32(6): 1333–1336.

[61] Corvol H, Hodges CA, Drumm ML, Guillot L. Moving beyond genetics: is FAM13A a major biological contri-butor in lung physiology and chronic lung diseases?, 2014, 51(10): 646–649.

[62] 熊明媚, 王健, 鐘南山, 盧文菊. 慢性阻塞性肺疾病相關(guān)基因組學(xué)研究. 中華結(jié)核和呼吸雜志, 2016, 39(1): 58–61.

Advances in genome-wide association study of chronic obstructive pulmonary disease

Guoqing Qian1,2,3

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and chronic airway inflammation, caused by a combination of environmental and genetic factors. It is the third leading cause of death worldwide. In recent years, researchers have applied the genome-wide association study (GWAS) and identified a large number of genetic variants associated with lung functions and potential drug targets for treating COPD. In this review, we summarize the results of GWAS studies and perform a review of the literature since 2007 to highlight the progress of GWAS on COPD. We discuss the challenges, the underlying mechanisms, and the possible drug targets, thereby providing insights on the pathogenesis and potential treatment strategies for COPD.

chronic obstructive pulmonary disease; lung function; genome-wide association study; genetic variant; locus; susceptibility gene; causal gene

2020-02-25;

2020-05-29

浙江省自然科學(xué)基金項目(編號：Q17H010001)和寧波市自然科學(xué)基金項目(編號：2017A610246)資助[Supported by the Natural Science Foundation of Zhejiang Province (No. Q17H010001), and the Natural Science Foundation of Ningbo City (No. 2017A610246)]

錢國清，博士，副主任醫(yī)師，研究方向：呼吸病學(xué)。E-mail: guoqing.qian@foxmail.com

10.16288/j.yczz.19-381

2020/6/29 11:04:48

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20200628.1028.001.html

(責(zé)任編委: 周鋼橋)