Blechter, BatelBatelBlechterWang, XiaoyuXiaoyuWangDai, JunchengJunchengDaiKarsonaki, ChristianaChristianaKarsonakiShi, JianxinJianxinShiShiraishi, KouyaKouyaShiraishiChoi, JiyeonJiyeonChoiMatsuo, KeitaroKeitaroMatsuoChen, Tzu-YuTzu-YuChenHung, Rayjean JRayjean JHungChen, KexinKexinChenShu, Xiao-OuXiao-OuShuKim, Young TaeYoung TaeKimChoudhury, Parichoy PalParichoy PalChoudhuryWilliams, JacobJacobWilliamsLandi, Maria TeresaMaria TeresaLandiLin, DongxinDongxinLinZheng, WeiWeiZhengYin, ZhihuaZhihuaYinZhou, BaosenBaosenZhouWang, JiucunJiucunWangSeow, Wei JieWei JieSeowSong, LeiLeiSongChang, I-ShouI-ShouChangHu, WeiWeiHuChien, Li-HsinLi-HsinChienCai, QiuyinQiuyinCaiHong, Yun-ChulYun-ChulHongKim, Hee NamHee NamKimWu, Yi-LongYi-LongWuWong, Maria PikMaria PikWongRichardson, Brian DouglasBrian DouglasRichardsonLi, ShilanShilanLiZhang, TongwuTongwuZhangBreeze, CharlesCharlesBreezeWang, ZhaomingZhaomingWangBassig, Bryan ABryan ABassigKim, Jin HeeJin HeeKimAlbanes, DemetriusDemetriusAlbanesWong Sm, Jason YyJason YyWong SmShin, Min-HoMin-HoShinChung, Lap PingLap PingChungYang, YangYangYangZheng, HongHongZhengDai, HongjiHongjiDaiYatabe, YasushiYasushiYatabeZhang, Xu-ChaoXu-ChaoZhangKim, Young-ChulYoung-ChulKimCaporaso, Neil ENeil ECaporasoChang, JiangJiangChangHo, James Chung ManJames Chung ManHoDaigo, YataroYataroDaigoMomozawa, YukihideYukihideMomozawaKamatani, YoichiroYoichiroKamataniKobayashi, MasashiMasashiKobayashiOkubo, KenichiKenichiOkuboHonda, TakayukiTakayukiHondaHosgood, H DeanH DeanHosgoodKunitoh, HideoHideoKunitohWatanabe, Shun-IchiShun-IchiWatanabeMiyagi, YoheiYoheiMiyagiMatsumoto, ShingoShingoMatsumotoHorinouchi, HidehitoHidehitoHorinouchiTsuboi, MasahiroMasahiroTsuboiHamamoto, RyujiRyujiHamamotoGoto, KoichiKoichiGotoTakahashi, AtsushiAtsushiTakahashiGoto, AkiteruAkiteruGotoMinamiya, YoshihiroYoshihiroMinamiyaHara, MegumiMegumiHaraNishida, YuichiroYuichiroNishidaTakeuchi, KenjiKenjiTakeuchiWakai, KenjiKenjiWakaiMatsuda, KoichiKoichiMatsudaMurakami, YoshinoriYoshinoriMurakamiShimizu, KimihiroKimihiroShimizuSuzuki, HiroyukiHiroyukiSuzukiSaito, MotonobuMotonobuSaitoOhtaki, YoichiYoichiOhtakiTanaka, KazumiKazumiTanakaWu, TangchunTangchunWuWei, FushengFushengWeiMachiela, Mitchell JMitchell JMachielaKim, Yeul HongYeul HongKimOh, In-JaeIn-JaeOhLee, Victor Ho FunVictor Ho FunLeeChang, Gee-ChenGee-ChenChangChen, Kuan-YuKuan-YuChenSu, Wu-ChouWu-ChouSuChen, Yuh-MinYuh-MinChenSeow, AdelineAdelineSeowPark, Jae YongJae YongParkKweon, Sun-SeogSun-SeogKweonGao, Yu-TangYu-TangGaoLiu, JianjunJianjunLiuSchwartz, Ann GAnn GSchwartzHoulston, RichardRichardHoulstonGorlov, Ivan PIvan PGorlovWu, XifengXifengWuYang, PingPingYangLam, StephenStephenLamTardon, AdoninaAdoninaTardonChen, ChuChuChenBojesen, Stig EStig EBojesenJohansson, MattiasMattiasJohanssonRisch, AngelaAngelaRischBickeböller, HeikeHeikeBickeböllerJi, Bu-TianBu-TianJiWichmann, H-ErichH-ErichWichmannChristiani, David CDavid CChristianiRennert, GadGadRennertArnold, Susanne MSusanne MArnoldBrennan, PaulPaulBrennanMcKay, JamesJamesMcKayField, John KJohn KFieldDavies, Michael P AMichael P ADaviesShete, Sanjay SSanjay SSheteLe Marchand, LoïcLoïcLe MarchandLiu, GeoffreyGeoffreyLiuAndrew, Angeline SAngeline SAndrewKiemeney, Lambertus ALambertus AKiemeneyZienolddiny-Narui, ShanShanZienolddiny-NaruiGrankvist, KjellKjellGrankvistCox, AngelaAngelaCoxTaylor, FionaFionaTaylorYuan, Jian-MinJian-MinYuanLazarus, PhilipPhilipLazarusSchabath, Matthew BMatthew BSchabathAldrich, Melinda CMelinda CAldrichJeon, Hyo-SungHyo-SungJeonJiang, Shih ShengShih ShengJiangChen, Chung-HsingChung-HsingChenHsiao, Chin-FuChin-FuHsiaoHu, ZhibinZhibinHuBurdett, LauraLauraBurdettYeager, MeredithMeredithYeagerHutchinson, AmyAmyHutchinsonHicks, BelyndaBelyndaHicksLiu, JiaJiaLiuBerndt, Sonja ISonja IBerndtWu, WeiWeiWuWang, JunwenJunwenWangLi, YuqingYuqingLiChoi, Jin EunJin EunChoiPark, Kyong HwaKyong HwaParkSung, Sook WhanSook WhanSungKang, Chang HyunChang HyunKangWang, Wen-ChangWen-ChangWangXu, JunJunXuGuan, PengPengGuanTan, WenWenTanYu, Chong-JenChong-JenYuYang, GongGongYangSihoe, Alan Dart LoonAlan Dart LoonSihoeChoi, Yi YoungYi YoungChoiPark, In KyuIn KyuParkHung, Hsiao-HanHsiao-HanHungVermeulen, Roel C HRoel C HVermeulenCheng, IonaIonaChengWu, JunjieJunjieWuTsai, Fang-YuFang-YuTsaiChan, John K CJohn K CChanLi, JihuaJihuaLiLin, Hsien-ChihHsien-ChihLinLiu, JieJieLiuSong, BaoBaoSongSawada, NorieNorieSawadaYamaji, TaikiTaikiYamajiWyatt, KathleenKathleenWyattMa, HongxiaHongxiaMaZhu, MengMengZhuWang, YifanYifanWangQi, TianchenTianchenQiLi, XuelianXuelianLiRen, YangwuYangwuRenChao, AnnAnnChaoIwasaki, MotokiMotokiIwasakiZhu, JunjieJunjieZhuWu, GuopingGuopingWuChen, Chih-YiChih-YiChenScD, Chien-Jen ChenChien-Jen ChenScDPAN-CHYR YANGStevens, Victoria LVictoria LStevensFraumeni, Joseph FJoseph FFraumeniLin, KuangKuangLinWalters, Robin GRobin GWaltersChen, ZhengmingZhengmingChenChatterjee, NilanjanNilanjanChatterjeeGorlova, Olga YOlga YGorlovaAmos, Christopher IChristopher IAmosShen, HongbingHongbingShenHsiung, Chao AgnesChao AgnesHsiungChanock, Stephen JStephen JChanockRothman, NathanielNathanielRothmanKohno, TakashiTakashiKohnoLan, QingQingLanZhang, HaoyuHaoyuZhang2026-04-132026-04-132025-10-01https://scholars.lib.ntu.edu.tw/handle/123456789/737124Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.enEast Asian never smokersGenome-wide association studiesLifetime absolute riskLung adenocarcinomaPolygenic risk scoresjournal article10.1093/jnci/djaf27241032288