Academic Journal
View in EDS

A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping.

Bibliographic Details
Title: A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping.
Authors: Kanchan K; Genomics and Precision Health Section, Laboratory of Allergic Diseases, The National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA., Erdogan-Yildirim Z; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Berke S; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA., Mukhopadhyay N; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Ray D; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Simpson CL; Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA., Bidinger JA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Curtis SW; Department of Human Genetics, Emory University, Atlanta, GA, USA., Butali A; Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Schwender H; Mathematisches Institut, Heinrich-Heine-Universität, Düsseldorf, Germany., Scott AF; Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA., Bailey-Wilson JE; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Beaty TH; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Leslie-Clarkson E; Department of Human Genetics, Emory University, Atlanta, GA, USA., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Ruczinski I; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Source: MedRxiv : the preprint server for health sciences [medRxiv] 2026 Jul 09. Date of Electronic Publication: 2026 Jul 09.
Publication Type: Journal Article; Preprint
Language: English
Journal Info: Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE
Abstract: Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromo-somes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.
Competing Interests: Conflict of Interest The authors do not have any conflicts of interest.
References: Am J Hum Genet. 2016 Apr 7;98(4):744-54. (PMID: 27018472)
F1000Res. 2016 Nov 30;5:2800. (PMID: 27990279)
Sci Rep. 2019 Jun 27;9(1):9354. (PMID: 31249361)
Genet Epidemiol. 2018 Oct;42(7):664-672. (PMID: 30277614)
Cleft Palate Craniofac J. 2017 Sep;54(5):571-581. (PMID: 27440051)
Nat Rev Genet. 2011 Mar;12(3):167-78. (PMID: 21331089)
Eur J Hum Genet. 2021 Jan;29(1):154-163. (PMID: 32873964)
Front Oral Biol. 2012;16:1-18. (PMID: 22759666)
Hum Genet. 2013 Jul;132(7):771-81. (PMID: 23512105)
Nat Protoc. 2009;4(8):1184-91. (PMID: 19617889)
Gigascience. 2019 Jul 1;8(7):. (PMID: 31289836)
PLoS Comput Biol. 2013;9(8):e1003118. (PMID: 23950696)
Biometrics. 2012 Sep;68(3):766-73. (PMID: 22150644)
Birth Defects Res C Embryo Today. 2008 Mar;84(1):16-29. (PMID: 18383123)
Annu Rev Genomics Hum Genet. 2023 Aug 25;24:151-176. (PMID: 37285546)
Nat Commun. 2017 Feb 24;8:14364. (PMID: 28232668)
Cell. 2023 May 11;186(10):2044-2061. (PMID: 37172561)
Am J Med Genet A. 2014 Aug;164A(8):2109-13. (PMID: 24715610)
J Dent Res. 2020 Dec;99(13):1461-1468. (PMID: 32758111)
Sci Rep. 2022 Jul 11;12(1):11743. (PMID: 35817949)
Genet Epidemiol. 1999;16(3):250-60. (PMID: 10096688)
Genet Epidemiol. 2022 Apr;46(3-4):182-198. (PMID: 35191549)
Am J Med Genet C Semin Med Genet. 2013 Nov;163C(4):246-58. (PMID: 24124047)
Nature. 2020 May;581(7809):434-443. (PMID: 32461654)
Nat Genet. 2010 Jan;42(1):24-6. (PMID: 20023658)
Nature. 2024 Jan;625(7993):92-100. (PMID: 38057664)
Nat Biotechnol. 2014 Mar;32(3):246-51. (PMID: 24531798)
J Oral Biol Craniofac Res. 2015 May-Aug;5(2):86-91. (PMID: 26258020)
Eur J Med Genet. 2014 Aug;57(8):381-93. (PMID: 24768816)
J Dent Res. 2017 Oct;96(11):1322-1329. (PMID: 28662356)
Dev Dyn. 2006 May;235(5):1152-66. (PMID: 16292776)
Genetics. 2020 May;215(1):231-241. (PMID: 32198180)
Hum Mol Genet. 2016 Jul 1;25(13):2862-2872. (PMID: 27033726)
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11484-9. (PMID: 14500911)
Am J Hum Genet. 2005 Apr;76(4):681-7. (PMID: 15719321)
Genes (Basel). 2019 Dec 07;10(12):. (PMID: 31817908)
Birth Defects Res A Clin Mol Teratol. 2014 Nov;100(11):895-904. (PMID: 25399767)
Hum Mol Genet. 2017 Feb 15;26(4):829-842. (PMID: 28087736)
Hum Mol Genet. 2024 Feb 28;33(6):543-551. (PMID: 38073250)
Oral Dis. 2010 Jan;16(1):3-10. (PMID: 19656316)
Nat Commun. 2018 Oct 2;9(1):4038. (PMID: 30279509)
Genet Med. 2020 Nov;22(11):1838-1850. (PMID: 32694869)
Cell Genom. 2023 Apr 06;3(5):100297. (PMID: 37228747)
Glob Med Genet. 2020 Dec;7(4):101-108. (PMID: 33693442)
Epidemiology. 2011 May;22(3):313-9. (PMID: 21423016)
Bioinformatics. 2011 Aug 1;27(15):2156-8. (PMID: 21653522)
Cleft Palate Craniofac J. 2024 Apr;61(4):697-705. (PMID: 36384317)
Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382)
J Dent Res. 2022 Apr;101(4):465-472. (PMID: 34689653)
Genome Res. 2002 Jun;12(6):996-1006. (PMID: 12045153)
HGG Adv. 2026 Sep 10;:100672. (PMID: 42723286)
Genet Epidemiol. 2014 Sep;38(6):516-22. (PMID: 25048299)
Genome Res. 2001 Jun;11(6):1005-17. (PMID: 11381028)
Hum Genet. 2017 Mar;136(3):275-286. (PMID: 28054174)
Am J Hum Genet. 2004 Aug;75(2):161-73. (PMID: 15185170)
BMC Oral Health. 2019 Dec 23;19(1):290. (PMID: 31870360)
Nat Genet. 2010 Jun;42(6):525-9. (PMID: 20436469)
Biometrics. 1999 Dec;55(4):997-1004. (PMID: 11315092)
Genome Res. 2002 Apr;12(4):656-64. (PMID: 11932250)
Nucleic Acids Res. 2026 Jan 6;54(D1):D1331-D1335. (PMID: 41251146)
Am J Med Genet A. 2009 Jun;149A(6):1149-58. (PMID: 19441124)
PLoS Genet. 2021 Jul 9;17(7):e1009584. (PMID: 34242216)
Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901)
Front Cell Dev Biol. 2021 Apr 16;9:621018. (PMID: 33937227)
Genome Res. 2009 Oct;19(10):1849-60. (PMID: 19541915)
Genet Epidemiol. 1996;13(5):423-49. (PMID: 8905391)
Nature. 2024 Sep;633(8028):47-57. (PMID: 39232149)
Hum Genet. 2020 Feb;139(2):215-226. (PMID: 31848685)
Genome Biol. 2016 Jul 29;17(1):166. (PMID: 27473438)
PLoS Genet. 2019 Oct 14;15(10):e1008357. (PMID: 31609978)
Genet Epidemiol. 2002 Nov;23(4):458-61; author reply 462-4. (PMID: 12432512)
Nature. 2001 May 10;411(6834):199-204. (PMID: 11346797)
Grant Information: R01 DE031855 United States DE NIDCR NIH HHS; U01 DE018993 United States DE NIDCR NIH HHS; T90 DE030853 United States DE NIDCR NIH HHS; R01 DE032319 United States DE NIDCR NIH HHS; R01 DE016148 United States DE NIDCR NIH HHS; R01 DE028300 United States DE NIDCR NIH HHS; R01 DE008559 United States DE NIDCR NIH HHS
Contributed Indexing: Keywords: Case-parent trios; genome-wide association studies; meta-analysis; orofacial clefts; read mapping; relative risk ratio; sequencing errors; sex-specific genetic effects; single nucleotide polymorphisms; whole genome sequencing
Entry Date(s): Date Created: 20260717 Date Completed: 20260725 Latest Revision: 20260922
Update Code: 20260922
PubMed Central ID: PMC13370597
DOI: 10.64898/2026.07.07.26357463
PMID: 42465919
Database: MEDLINE
Description
DOI:10.64898/2026.07.07.26357463