{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:16:02Z","timestamp":1792692962509,"version":"4.5.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The association between autophagy, structural alterations of the aortic wall, and endothelial dysfunction in humans has yet to be fully elucidated. The family of <jats:italic>ULK<\/jats:italic> (UNC51-like) enzymes plays critical roles in autophagy and development. This study aimed to evaluate the association between <jats:italic>ULK<\/jats:italic> gene family members and patient age of first type B aortic dissection (TBAD) onset.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The genotype data in a TBAD cohort from China and the related summary-level datasets were analyzed. We applied the sequence kernel association test (SKAT) to test the association between single-nucleotide polymorphisms (SNPs) and age of first onset of TBAD controlling for gender, hypertension, and renal function. Next, we performed a 2-sample Mendelian randomization (MR) to explore the potential causal relationship between <jats:italic>ULK4<\/jats:italic> and early onset of TBAD at the level of gene expression coupled with DNA methylation with genetic variants as instrumental variables.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 159 TBAD patients with 1,180,097 SNPs were included. Concerning the association between the <jats:italic>ULK<\/jats:italic> gene family and the age of first onset of the TBAD, only <jats:italic>ULK4<\/jats:italic> was found to be significant according to SKAT analysis (q-<jats:italic>FDR<\/jats:italic> = 0.0088). From 2-sample MR, the high level of <jats:italic>ULK4<\/jats:italic> gene expression was related to a later age of first onset of TBAD (<jats:italic>\u03b2<\/jats:italic> = 4.58, <jats:italic>p<\/jats:italic> = 0.0214).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> This is the first study of the <jats:italic>ULK<\/jats:italic> gene family in TBAD, regarding the association with the first onset age. We demonstrated that the <jats:italic>ULK4<\/jats:italic> gene is associated with the time of onset of TBAD based on both the SKAT and 2-sample MR analyses.<\/jats:p>","DOI":"10.3389\/fgene.2022.956866","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T07:23:05Z","timestamp":1662103385000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of genetic variants in ULK4 with the age of first onset of type B aortic dissection"],"prefix":"10.3389","volume":"13","author":[{"given":"Lihong","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruihan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyue","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"B2","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/s0741-5214(97)70261-1","article-title":"Familial thoracic aortic dilatations and dissections: A case control study","volume":"25","author":"Biddinger","year":"1997","journal-title":"J. Vasc. Surg."},{"key":"B3","doi-asserted-by":"publisher","first-page":"758","DOI":"10.4161\/auto.8709","article-title":"Evolution of Atg1 function and regulation","volume":"5","author":"Chan","year":"2009","journal-title":"Autophagy"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1161\/ATVBAHA.118.311727","article-title":"Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms","volume":"39","author":"Cl\u00e9ment","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"6806","DOI":"10.21037\/jtd-20-2421","article-title":"Acute stanford type B aortic dissection\u2014Who benefits from genetic testing?","volume":"12","author":"Erhart","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1146\/annurev-genom-090314-050016","article-title":"Mendelian randomization: New applications in the coming age of hypothesis-free causality","volume":"16","author":"Evans","year":"2015","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"eaat8127","DOI":"10.1126\/science.aat8127","article-title":"Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder","volume":"362","author":"Gandal","year":"2018","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.ajhg.2016.06.034","article-title":"Genetic variants in LRP1 and ULK4 are associated with acute aortic dissections","volume":"99","author":"Guo","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1001\/jama.283.7.897","article-title":"The international registry of acute aortic dissection (IRAD): New insights into an old disease","volume":"283","author":"Hagan","year":"2000","journal-title":"Jama"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"elife"},{"key":"B11","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1177\/1538574420983652","article-title":"Ten-year clinical characteristics and early outcomes of type B aortic dissection patients with thoracic endovascular aortic repair","volume":"55","author":"Huang","year":"2021","journal-title":"Vasc. Endovasc. Surg."},{"key":"B12","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1016\/j.ajhg.2013.04.015","article-title":"Sequence kernel association tests for the combined effect of rare and common variants","volume":"92","author":"Ionita-Laza","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1016\/j.jvs.2016.09.033","article-title":"Predictors of aortic growth in uncomplicated type B aortic dissection from the acute dissection stent grafting or best medical treatment (ADSORB) database","volume":"65","author":"Kamman","year":"2017","journal-title":"J. Vasc. Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1021\/jacs.9b10458","article-title":"High-resolution structure and inhibition of the schizophrenia-linked pseudokinase ULK4","volume":"142","author":"Khamrui","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"B15","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/ng.384","article-title":"Genome-wide association study of blood pressure and hypertension","volume":"41","author":"Levy","year":"2009","journal-title":"Nat. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1313646","DOI":"10.1080\/23262133.2017.1313646","article-title":"Multiple roles of Ulk4 in neurogenesis and brain function","volume":"4","author":"Liu","year":"2017","journal-title":"Neurogenesis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"eaah5770","DOI":"10.1126\/scisignal.aah5770","article-title":"Wdpcp promotes epicardial EMT and epicardium-derived cell migration to facilitate coronary artery remodeling","volume":"11","author":"Liu","year":"2018","journal-title":"Sci. Signal."},{"key":"B18","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.yexcr.2009.10.018","article-title":"Identification of a novel serine\/threonine kinase ULK3 as a positive regulator of Hedgehog pathway","volume":"316","author":"Maloverjan","year":"2010","journal-title":"Exp. Cell Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4588","DOI":"10.1096\/fj.201700136RR","article-title":"The nuclear receptor NOR\u20101\/NR4A3 regulates the multifunctional glycoprotein vitronectin in human vascular smooth muscle cells","volume":"31","author":"Mart\u00ed\u2010P\u00e0mies","year":"2017","journal-title":"FASEB J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11748-017-0831-8","article-title":"Guidelines for the management of thoracic aortic disease in 2017","volume":"67","author":"Mokashi","year":"2019","journal-title":"Gen. Thorac. Cardiovasc. Surg."},{"key":"B21","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/S0140-6736(14)61005-9","article-title":"Management of acute aortic dissection","volume":"385","author":"Nienaber","year":"2015","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"182","DOI":"10.3390\/biom10020182","article-title":"The genetics of thoracic aortic aneurysms and dissection: A clinical perspective","volume":"10","author":"Ostberg","year":"2020","journal-title":"Biomolecules"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1016\/S0140-6736(96)09372-5","article-title":"Aortic dissection","volume":"349","author":"Pr\u00eatre","year":"1997","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1016\/j.jacc.2010.01.076","article-title":"Biomarkers in acute aortic dissection and other aortic syndromes","volume":"56","author":"Ranasinghe","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1016\/j.jvs.2020.10.080","article-title":"Characterization of syndromic, nonsyndromic familial, and sporadic type B aortic dissection","volume":"73","author":"Shalhub","year":"2021","journal-title":"J. Vasc. Surg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.athoracsur.2019.07.004","article-title":"Type B aortic dissection in young individuals with confirmed and presumed heritable thoracic aortic disease","volume":"109","author":"Shalhub","year":"2020","journal-title":"Ann. Thorac. Surg."},{"key":"B27","doi-asserted-by":"publisher","first-page":"D77","DOI":"10.1093\/nar\/gkm840","article-title":"COXPRESdb: A database of coexpressed gene networks in mammals","volume":"36","author":"Takeshi","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1093\/nar\/gks1014","article-title":"Motoike IN, kengo K: COXPRESdb: A database of comparative gene coexpression networks of eleven species for mammals","volume":"41","author":"Takeshi","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"D55-D62","DOI":"10.1093\/nar\/gky1155","article-title":"COXPRESdb v7: A gene coexpression database for 11 animal species supported by 23 coexpression platforms for technical evaluation and evolutionary inference","volume":"47","author":"Takeshi","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"eaat8464","DOI":"10.1126\/science.aat8464","article-title":"Comprehensive functional genomic resource and integrative model for the human brain","volume":"362","author":"Wang","year":"2018","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1177\/1538574412443315","article-title":"Gene expression profiling in acute Stanford type B aortic dissection","volume":"46","author":"Wang","year":"2012","journal-title":"Vasc. Endovasc. Surg."},{"key":"B32","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ajhg.2011.05.029","article-title":"Rare-variant association testing for sequencing data with the sequence kernel association test","volume":"89","author":"Wu","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1038\/s41467-018-03371-0","article-title":"Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits","volume":"9","author":"Wu","year":"2018","journal-title":"Nat. Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/s41418-019-0480-9","article-title":"Autophagy and disease: Unanswered questions","volume":"27","author":"Yang","year":"2020","journal-title":"Cell Death Differ."},{"key":"B35","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1101\/gad.519709","article-title":"Autophagy mediates the mitotic senescence transition","volume":"23","author":"Young","year":"2009","journal-title":"Genes Dev."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.956866\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T07:23:11Z","timestamp":1662103391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.956866\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,2]]},"references-count":35,"alternative-id":["10.3389\/fgene.2022.956866"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.956866","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,2]]},"article-number":"956866"}}