{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:13:51Z","timestamp":1789733631109,"version":"4.0.1"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2019M650447"],"award-info":[{"award-number":["2019M650447"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81701930"],"award-info":[{"award-number":["81701930"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81571924"],"award-info":[{"award-number":["81571924"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970898"],"award-info":[{"award-number":["81970898"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31671312"],"award-info":[{"award-number":["31671312"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Craniofacial microsomia (CFM, OMIM%164\u2009210) is one of the most common congenital facial abnormalities worldwide, but it\u2019s genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P\u2009&amp;lt;\u20095\u2009\u00d7\u200910\u22128) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P\u2009=\u20097.22\u2009\u00d7\u200910\u221258, odds ratio\u2009=\u20093.15, 95% confidence interval (CI) 2.74\u20133.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father\u2019s smoking increases CFM risk as evidenced by interaction parameter of \u22120.324 (95% CI \u22120.578 to \u22120.070, P\u2009=\u20090.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father\u2019s smoking is a key environmental risk factor for CFM through interacting with genetic factors.<\/jats:p>","DOI":"10.1093\/hmg\/ddab055","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T14:48:04Z","timestamp":1613573284000},"page":"1045-1056","source":"Crossref","is-referenced-by-count":13,"title":["Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis"],"prefix":"10.1093","volume":"30","author":[{"given":"Xiaopeng","family":"Xu","sequence":"first","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510320, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Mao","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Shi","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Yan","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintian","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zha","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouqin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huisheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510320, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Biao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine and Engineering, Beihang University, Beijing 100191, China"},{"name":"Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"issue":"Suppl 1","key":"2021060211411564400_ref1","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1097\/SCS.0b013e318193d5d5","article-title":"Hemifacial microsomia: from gestation to childhood","volume":"20","author":"Werler","year":"2009","journal-title":"J. Craniofac. Surg."},{"key":"2021060211411564400_ref2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/ajmg.c.31383","article-title":"Perspectives and challenges in advancing research into craniofacial anomalies","volume":"163C","author":"Cox","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021060211411564400_ref3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/PRS.0b013e3181f95d15","article-title":"A phenotypic assessment tool for craniofacial microsomia","volume":"127","author":"Birgfeld","year":"2011","journal-title":"Plast. Reconstr. Surg."},{"key":"2021060211411564400_ref4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1601-6343.2007.00391.x","article-title":"Review of the etiologic heterogeneity of the oculo-auriculo-vertebral spectrum (Hemifacial Microsomia)","volume":"10","author":"Hartsfield","year":"2007","journal-title":"Orthod. Craniofac. Res."},{"key":"2021060211411564400_ref5","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1177\/0022034518795609","article-title":"Etiology and pathogenesis of hemifacial microsomia","volume":"97","author":"Chen","year":"2018","journal-title":"J. Dent. Res."},{"key":"2021060211411564400_ref6","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1136\/jmedgenet-2014-102476","article-title":"Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update","volume":"51","author":"Beleza-Meireles","year":"2014","journal-title":"J. Med. Genet."},{"key":"2021060211411564400_ref7","article-title":"Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia","volume":"7","author":"Zhang","year":"2016","journal-title":"Nat. Commun."},{"key":"2021060211411564400_ref8","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0096788","article-title":"OTX2 duplication is implicated in hemifacial microsomia","volume":"9","author":"Zielinski","year":"2014","journal-title":"PLoS One"},{"key":"2021060211411564400_ref9","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1101\/gad.9.21.2646","article-title":"Mouse Otx2 functions in the formation and patterning of rostral head","volume":"9","author":"Matsuo","year":"1995","journal-title":"Genes Dev."},{"key":"2021060211411564400_ref10","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1242\/dev.040048","article-title":"Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development","volume":"137","author":"Minoux","year":"2010","journal-title":"Development"},{"key":"2021060211411564400_ref11","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/bdrc.21096","article-title":"Thalidomide-induced teratogenesis: history and mechanisms","volume":"105","author":"Vargesson","year":"2015","journal-title":"Birth Defects Res C Embryo Today"},{"key":"2021060211411564400_ref12","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/0030-4220(73)90070-4","article-title":"The pathogenesis of the first and second branchial arch syndrome","volume":"35","author":"Poswillo","year":"1973","journal-title":"Oral Surg. Oral Med. Oral Pathol."},{"key":"2021060211411564400_ref13","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1159\/000145741","article-title":"Effects of retinoic acid on the development of the facial skeleton in hamsters: early changes involving cranial neural crest cells","volume":"116","author":"Wiley","year":"1983","journal-title":"Acta Anat. (Basel)"},{"key":"2021060211411564400_ref14","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ajog.2015.09.082","article-title":"New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects","volume":"214","author":"Dong","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"2021060211411564400_ref15","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/bdrb.20321","article-title":"Altered gene expression in rat cranial neural crest cells exposed to a teratogenic glucose concentration in vitro: paradoxical downregulation of antioxidative defense genes","volume":"92","author":"Wentzel","year":"2011","journal-title":"Birth Defects Res. B Dev. Reprod. Toxicol."},{"key":"2021060211411564400_ref16","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1007\/s10654-016-0171-5","article-title":"Maternal alcohol binge-drinking in the first trimester and the risk of orofacial clefts in offspring: a large population-based pooling study","volume":"31","author":"DeRoo","year":"2016","journal-title":"Eur. J. Epidemiol."},{"key":"2021060211411564400_ref17","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/ppe.12131","article-title":"Maternal alcohol consumption during pregnancy and the risk of orofacial clefts in infants: a systematic review and meta-analysis","volume":"28","author":"Bell","year":"2014","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"2021060211411564400_ref18","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/bs.ctdb.2015.12.010","article-title":"Gene-environment interactions and the etiology of birth defects","volume":"116","author":"Krauss","year":"2016","journal-title":"Curr. Top. Dev. Biol."},{"key":"2021060211411564400_ref19","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv036","article-title":"Prediction of breast cancer risk based on profiling with common genetic variants","volume":"107","author":"Mavaddat","year":"2015","journal-title":"J. Natl. Cancer Inst."},{"key":"2021060211411564400_ref20","doi-asserted-by":"publisher","DOI":"10.1126\/science.aas9536","article-title":"Spatiotemporal structure of cell fate decisions in murine neural crest","volume":"364","author":"Soldatov","year":"2019","journal-title":"Science"},{"key":"2021060211411564400_ref21","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1242\/dev.105445","article-title":"Establishing neural crest identity: a gene regulatory recipe","volume":"142","author":"Simoes-Costa","year":"2015","journal-title":"Development"},{"key":"2021060211411564400_ref22","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1016\/j.biomaterials.2012.11.051","article-title":"The effect of overexpression of Dlx2 on the migration, proliferation and osteogenic differentiation of cranial neural crest stem cells","volume":"34","author":"Dai","year":"2013","journal-title":"Biomaterials"},{"key":"2021060211411564400_ref23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal2913","article-title":"Gene bivalency at Polycomb domains regulates cranial neural crest positional identity","volume":"355","author":"Minoux","year":"2017","journal-title":"Science"},{"key":"2021060211411564400_ref24","doi-asserted-by":"crossref","first-page":"5703","DOI":"10.1242\/dev.01444","article-title":"An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning","volume":"131","author":"Crump","year":"2004","journal-title":"Development"},{"key":"2021060211411564400_ref25","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1002\/dvdy.20882","article-title":"Sema3D and Sema7A have distinct expression patterns in chick embryonic development","volume":"235","author":"Bao","year":"2006","journal-title":"Dev. Dyn."},{"key":"2021060211411564400_ref26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.gde.2019.06.004","article-title":"Integrating chemical and mechanical signals in neural crest cell migration","volume":"57","author":"Shellard","year":"2019","journal-title":"Curr. Opin. Genet. Dev."},{"key":"2021060211411564400_ref27","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1002\/ijc.31748","article-title":"Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients\u2019 survival and indicate proteins targetable at onset of disease","volume":"143","author":"Esposito","year":"2018","journal-title":"Int. J. Cancer"},{"key":"2021060211411564400_ref28","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1073\/pnas.0908423107","article-title":"FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex","volume":"107","author":"Ikenouchi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021060211411564400_ref29","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1083\/jcb.200807096","article-title":"An essential role for p120-catenin in Src- and Rac1-mediated anchorage-independent cell growth","volume":"184","author":"Dohn","year":"2009","journal-title":"J. Cell Biol."},{"key":"2021060211411564400_ref30","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.semcdb.2004.05.005","article-title":"Cell surface receptors in lysophospholipid signaling","volume":"15","author":"Anliker","year":"2004","journal-title":"Semin. Cell Dev. Biol."},{"key":"2021060211411564400_ref31","doi-asserted-by":"crossref","first-page":"13384","DOI":"10.1073\/pnas.97.24.13384","article-title":"Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior","volume":"97","author":"Contos","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021060211411564400_ref32","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.mcn.2003.09.001","article-title":"LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease","volume":"24","author":"Harrison","year":"2003","journal-title":"Mol. Cell Neurosci."},{"key":"2021060211411564400_ref33","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0092-8674(00)81537-8","article-title":"Shroom, a PDZ domain-containing actin-binding protein, is required for neural tube morphogenesis in mice","volume":"99","author":"Hildebrand","year":"1999","journal-title":"Cell"},{"key":"2021060211411564400_ref34","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1242\/dev.019646","article-title":"Shroom3-mediated recruitment of Rho kinases to the apical cell junctions regulates epithelial and neuroepithelial planar remodeling","volume":"135","author":"Nishimura","year":"2008","journal-title":"Development"},{"key":"2021060211411564400_ref35","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1242\/bio.20147450","article-title":"The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice","volume":"3","author":"Das","year":"2014","journal-title":"Biol Open"},{"key":"2021060211411564400_ref36","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.1073\/pnas.1419368112","article-title":"Neural crest cell-derived VEGF promotes embryonic jaw extension","volume":"112","author":"Wiszniak","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021060211411564400_ref37","doi-asserted-by":"crossref","first-page":"10260","DOI":"10.1002\/jcp.27695","article-title":"Lysyl oxidase-like 2 is a regulator of angiogenesis through modulation of endothelial-to-mesenchymal transition","volume":"234","author":"Jong","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"2021060211411564400_ref38","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1158\/0008-5472.465.65.2","article-title":"CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers","volume":"65","author":"Kryczek","year":"2005","journal-title":"Cancer Res."},{"key":"2021060211411564400_ref39","doi-asserted-by":"crossref","first-page":"3155","DOI":"10.1182\/blood-2004-07-2563","article-title":"The role of CXCL12 in the organ-specific process of artery formation","volume":"105","author":"Ara","year":"2005","journal-title":"Blood"},{"key":"2021060211411564400_ref40","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1124\/jpet.114.219535","article-title":"Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids","volume":"351","author":"Agbor","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021060211411564400_ref41","doi-asserted-by":"crossref","first-page":"8386","DOI":"10.1073\/pnas.140087397","article-title":"The transcription factor EPAS-1\/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling","volume":"97","author":"Peng","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021060211411564400_ref42","doi-asserted-by":"crossref","DOI":"10.1038\/srep44988","article-title":"LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway","volume":"7","author":"Cuevas","year":"2017","journal-title":"Sci. Rep."},{"key":"2021060211411564400_ref43","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ydbio.2009.06.031","article-title":"A role for chemokine signaling in neural crest cell migration and craniofacial development","volume":"333","author":"Olesnicky Killian","year":"2009","journal-title":"Dev. Biol."},{"key":"2021060211411564400_ref44","first-page":"582","article-title":"Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations","volume":"143","author":"Escot","year":"2016","journal-title":"Development"},{"key":"2021060211411564400_ref45","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1242\/dev.131912","article-title":"Hypoxia promotes production of neural crest cells in the embryonic head","volume":"143","author":"Scully","year":"2016","journal-title":"Development"},{"key":"2021060211411564400_ref46","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1056\/NEJM198510033131401","article-title":"Retinoic acid embryopathy","volume":"313","author":"Lammer","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"2021060211411564400_ref47","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1136\/jmedgenet-2018-105313","article-title":"Evaluation of polygenic risk scores for ovarian cancer risk prediction in a prospective cohort study","volume":"55","author":"Yang","year":"2018","journal-title":"J. Med. Genet."},{"key":"2021060211411564400_ref48","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1093\/ije\/dyx242","article-title":"Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium","volume":"47","author":"Rudolph","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"2021060211411564400_ref49","first-page":"22","article-title":"Polygenic risk scores in neurodegenerative diseases: a review","volume-title":"Curr. Genet. Med. Rep.","author":"Ibanez","year":"2019"},{"key":"2021060211411564400_ref50","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/19485565.2014.952705","article-title":"A polygenic risk score associated with measures of depressive symptoms among older adults","volume":"60","author":"Levine","year":"2014","journal-title":"Biodemography Soc. Biol."},{"key":"2021060211411564400_ref51","doi-asserted-by":"crossref","first-page":"5997","DOI":"10.1073\/pnas.1919976117","article-title":"Assessing thyroid cancer risk using polygenic risk scores","volume":"117","author":"Liyanarachchi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021060211411564400_ref52","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3389\/fgene.2019.00267","article-title":"Machine learning SNP based prediction for precision medicine","volume":"10","author":"Ho","year":"2019","journal-title":"Front. Genet."},{"key":"2021060211411564400_ref53","article-title":"Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"2021060211411564400_ref54","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13073-020-00742-5","article-title":"Polygenic risk scores: from research tools to clinical instruments","volume":"12","author":"Lewis","year":"2020","journal-title":"Genome Med."},{"key":"2021060211411564400_ref55","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1093\/ije\/dyv048","article-title":"DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring","volume":"44","author":"Kupers","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"2021060211411564400_ref56","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1007\/s00439-011-1102-x","article-title":"Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence","volume":"131","author":"Yoon","year":"2012","journal-title":"Hum. Genet."},{"key":"2021060211411564400_ref57","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/humupd\/dmr022","article-title":"Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls","volume":"17","author":"Hackshaw","year":"2011","journal-title":"Hum. Reprod. Update"},{"key":"2021060211411564400_ref58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/bdrc.20117","article-title":"Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects","volume":"84","author":"Shi","year":"2008","journal-title":"Birth Defects Res C Embryo Today"},{"key":"2021060211411564400_ref59","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1542\/peds.2010-3041","article-title":"Secondhand smoke and adverse fetal outcomes in nonsmoking pregnant women: a meta-analysis","volume":"127","author":"Leonardi-Bee","year":"2011","journal-title":"Pediatrics"},{"key":"2021060211411564400_ref60","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1136\/tobaccocontrol-2018-054288","article-title":"Secondhand smoke exposure during pregnancy: a cross-sectional analysis of data from Demographic and Health Survey from 30 low-income and middle-income countries","volume":"28","author":"Reece","year":"2019","journal-title":"Tob. Control."},{"key":"2021060211411564400_ref61","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1001\/archotol.127.3.265","article-title":"Craniofacial, temporal bone, and audiologic abnormalities in the spectrum of hemifacial microsomia","volume":"127","author":"Rahbar","year":"2001","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"2021060211411564400_ref62","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2021060211411564400_ref63","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"Locus zoom: regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"2021060211411564400_ref64","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"GCTA: a tool for genome-wide complex trait analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2021060211411564400_ref65","first-page":"62","article-title":"An epidemiological investigation of anotia and microtia in China during 1988-1992","volume":"35","author":"Zhu","year":"2000","journal-title":"Zhonghua Er Bi Yan Hou Ke Za Zhi"},{"key":"2021060211411564400_ref66","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s13059-018-1519-9","article-title":"The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions","volume":"19","author":"Wang","year":"2018","journal-title":"Genome Biol."},{"key":"2021060211411564400_ref67","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."},{"key":"2021060211411564400_ref68","doi-asserted-by":"crossref","first-page":"5890","DOI":"10.1038\/ncomms6890","article-title":"Biological interpretation of genome-wide association studies using predicted gene functions","volume":"6","author":"Pers","year":"2015","journal-title":"Nat. Commun."},{"key":"2021060211411564400_ref69","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2021060211411564400_ref70","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1093\/bioinformatics\/btw777","article-title":"Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R","volume":"33","author":"McCarthy","year":"2017","journal-title":"Bioinformatics"},{"key":"2021060211411564400_ref71","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1186\/s13059-019-1874-1","article-title":"Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression","volume":"20","author":"Hafemeister","year":"2019","journal-title":"Genome Biol."},{"key":"2021060211411564400_ref72","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"2021060211411564400_ref73","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genomics"},{"key":"2021060211411564400_ref74","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/ng.375","article-title":"The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line","volume":"41","author":"FANTOM Consortium","year":"2009","journal-title":"Nat. Genet."},{"key":"2021060211411564400_ref75","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1006378","article-title":"clusterExperiment and RSEC: a Bioconductor package and framework for clustering of single-cell and other large gene expression datasets","volume":"14","author":"Risso","year":"2018","journal-title":"PLoS Comput. Biol."},{"key":"2021060211411564400_ref76","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2021060211411564400_ref77","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"2021060211411564400_ref78","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giz082","article-title":"PRSice-2: polygenic risk score software for biobank-scale data","volume":"8","author":"Choi","year":"2019","journal-title":"Gigascience"},{"key":"2021060211411564400_ref79","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: an open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"Robin","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2021060211411564400_ref80","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1093\/aje\/kwz175","article-title":"Case-only analysis of gene-environment interactions using polygenic risk scores","volume":"188","author":"Meisner","year":"2019","journal-title":"Am. J. Epidemiol."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab055\/37017554\/ddab055.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/11\/1045\/38445582\/ddab055.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/11\/1045\/38445582\/ddab055.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T10:00:21Z","timestamp":1697882421000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/11\/1045\/6145950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":80,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,2,22]]},"published-print":{"date-parts":[[2021,5,31]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab055","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6,1]]},"published":{"date-parts":[[2021,2,22]]}}}