{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:04:17Z","timestamp":1768565057219,"version":"3.49.0"},"posted":{"date-parts":[[2023,7,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":62,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Aneuploidy, the state of a cell containing extra or missing chromosomes, frequently arises during human meiosis and is the primary cause of early miscarriage and maternal age-related in vitro fertilization (IVF) failure. IVF patients exhibit significant variability in aneuploidy rates, although the exact genetic causes of the variability in aneuploid egg production remain unclear. Preimplantation genetic testing for aneuploidy (PGT-A) using ultra-low coverage whole-genome sequencing (ulc-WGS) is a standard test for identifying and selecting IVF-derived embryos with a normal chromosome complement. The wealth of embryo aneuploidy data and ulc-WGS data from PGT-A has potential for discovering variants in paternal genomes that are associated with aneuploidy risk in their embryos.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using ulc-WGS data from \u223c10,000 PGT-A biopsies, we imputed genotype likelihoods of genetic variants in parental genomes. We then used the imputed variants and aneuploidy calls from the embryos to perform a genome-wide association study of aneuploidy incidence. Finally, we carried out functional evaluation of the identified candidate gene in a mouse oocyte system.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified one locus on chromosome 3 that is significantly associated with maternal meiotic aneuploidy risk. One candidate gene,\n                    <jats:italic>CCDC66,<\/jats:italic>\n                    encompassed by this locus, is involved in chromosome segregation during meiosis. Using mouse oocytes, we showed that CCDC66 regulates meiotic progression and chromosome segregation fidelity, especially in older mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our work extended the research utility of PGT-A ulc-WGS data by allowing robust association testing and improved the understanding of the genetic contribution to maternal meiotic aneuploidy risk. Importantly, we introduce a generalizable method that can be leveraged for similar association studies using ulc-WGS data.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.07.22.23292618","type":"posted-content","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T14:30:21Z","timestamp":1690209021000},"source":"Crossref","is-referenced-by-count":0,"title":["Identifying risk genes for embryo aneuploidy using ultra-low coverage whole-genome sequencing"],"prefix":"10.64898","author":[{"given":"Siqi","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansour","family":"Aboelenain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Ariad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Haywood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Wageman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlena","family":"Duke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishee","family":"Bag","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Viotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mandy","family":"Katz-Jaffe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajiv C.","family":"McCoy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Schindler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinchuan","family":"Xing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023072604300808000_2023.07.22.23292618v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/35066065"},{"key":"2023072604300808000_2023.07.22.23292618v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.11.004"},{"issue":"3","key":"2023072604300808000_2023.07.22.23292618v1.3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.rbmo.2018.11.023","article-title":"Incidence and origin of meiotic whole and segmental chromosomal aneuploidies detected by karyomapping","volume":"38","year":"2019","journal-title":"Reproductive BioMedicine Online"},{"key":"2023072604300808000_2023.07.22.23292618v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2010.08.014"},{"key":"2023072604300808000_2023.07.22.23292618v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa3337"},{"key":"2023072604300808000_2023.07.22.23292618v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gax018"},{"issue":"9","key":"2023072604300808000_2023.07.22.23292618v1.7","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1093\/humrep\/deaa148","article-title":"Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk","volume":"35","year":"2020","journal-title":"Hum Reprod"},{"issue":"10","key":"2023072604300808000_2023.07.22.23292618v1.8","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1007\/s00439-022-02450-z","article-title":"Predicting embryonic aneuploidy rate in IVF patients using whole-exome sequencing","volume":"141","year":"2022","journal-title":"Hum Genet"},{"key":"2023072604300808000_2023.07.22.23292618v1.9","unstructured":"Choe, J. and A.L. Shanks , In Vitro Fertilization, in StatPearls. 2023: Treasure Island (FL)."},{"key":"2023072604300808000_2023.07.22.23292618v1.10","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.ss6707a1"},{"issue":"10","key":"2023072604300808000_2023.07.22.23292618v1.11","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nrg.2016.97","article-title":"Prenatal and pre-implantation genetic diagnosis","volume":"17","year":"2016","journal-title":"Nat Rev Genet"},{"key":"2023072604300808000_2023.07.22.23292618v1.12","doi-asserted-by":"crossref","unstructured":"Viotti, M ., Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements . Genes (Basel), 2020. 11(6).","DOI":"10.3390\/genes11060602"},{"issue":"1","key":"2023072604300808000_2023.07.22.23292618v1.13","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13073-023-01158-7","article-title":"Ultra-low-coverage genome-wide association study-insights into gestational age using 17,844 embryo samples with preimplantation genetic testing","volume":"15","year":"2023","journal-title":"Genome Med"},{"key":"2023072604300808000_2023.07.22.23292618v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0127-1"},{"key":"2023072604300808000_2023.07.22.23292618v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.06.005"},{"key":"2023072604300808000_2023.07.22.23292618v1.16","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.190221"},{"key":"2023072604300808000_2023.07.22.23292618v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0016-z"},{"key":"2023072604300808000_2023.07.22.23292618v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.016"},{"key":"2023072604300808000_2023.07.22.23292618v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04951-w"},{"key":"2023072604300808000_2023.07.22.23292618v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109307118"},{"key":"2023072604300808000_2023.07.22.23292618v1.21","doi-asserted-by":"crossref","unstructured":"Tyc, K.M. , et al., Analysis of DNA variants in miRNAs and miRNA 3\u2019UTR binding sites in female infertility patients. Lab Invest, 2020.","DOI":"10.1038\/s41374-020-00498-x"},{"key":"2023072604300808000_2023.07.22.23292618v1.22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"2023072604300808000_2023.07.22.23292618v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2023072604300808000_2023.07.22.23292618v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.04.018"},{"key":"2023072604300808000_2023.07.22.23292618v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2924"},{"key":"2023072604300808000_2023.07.22.23292618v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr509"},{"key":"2023072604300808000_2023.07.22.23292618v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00756-0"},{"key":"2023072604300808000_2023.07.22.23292618v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2023072604300808000_2023.07.22.23292618v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts610"},{"key":"2023072604300808000_2023.07.22.23292618v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/BIOINFORMATICS\/BTAB186"},{"key":"2023072604300808000_2023.07.22.23292618v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"2023072604300808000_2023.07.22.23292618v1.32","doi-asserted-by":"crossref","unstructured":"Aboelenain, M. and K. Schindler , Aurora kinase B inhibits aurora kinase A to control maternal mRNA translation in mouse oocytes. Development, 2021. 148(21).","DOI":"10.1242\/dev.199560"},{"key":"2023072604300808000_2023.07.22.23292618v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0028-3"},{"issue":"6581","key":"2023072604300808000_2023.07.22.23292618v1.34","doi-asserted-by":"crossref","first-page":"eabj3944","DOI":"10.1126\/science.abj3944","article-title":"Mechanism of spindle pole organization and instability in human oocytes","volume":"375","year":"2022","journal-title":"Science"},{"key":"2023072604300808000_2023.07.22.23292618v1.35","doi-asserted-by":"crossref","unstructured":"Blengini, C.S. and K. Schindler , Immunofluorescence technique to detect subcellular structures critical to oocyte maturation. Mouse Oocyte Development: Methods and Protocols, 2018: p. 67\u201376.","DOI":"10.1007\/978-1-4939-8603-3_8"},{"issue":"11","key":"2023072604300808000_2023.07.22.23292618v1.36","doi-asserted-by":"crossref","first-page":"e13489","DOI":"10.1111\/acel.13489","article-title":"Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B","volume":"20","year":"2021","journal-title":"Aging Cell"},{"key":"2023072604300808000_2023.07.22.23292618v1.37","doi-asserted-by":"crossref","unstructured":"Stein, P. and K. Schindler , Mouse oocyte microinjection, maturation and ploidy assessment. J Vis Exp, 2011(53).","DOI":"10.3791\/2851-v"},{"issue":"D1","key":"2023072604300808000_2023.07.22.23292618v1.38","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gkz836","article-title":"The International Genome Sample Resource (IGSR) collection of open human genomic variation resources","volume":"48","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"2023072604300808000_2023.07.22.23292618v1.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000888"},{"issue":"7","key":"2023072604300808000_2023.07.22.23292618v1.40","doi-asserted-by":"crossref","first-page":"e3001708","DOI":"10.1371\/journal.pbio.3001708","article-title":"The ciliopathy protein CCDC66 controls mitotic progression and cytokinesis by promoting microtubule nucleation and organization","volume":"20","year":"2022","journal-title":"PLoS Biol"},{"key":"2023072604300808000_2023.07.22.23292618v1.41","doi-asserted-by":"crossref","unstructured":"Conkar, D. , et al., CCDC66 regulates primary cilium length and signaling competence via multisite interactions with transition zone and axonemal proteins. biorxiv, 2022.","DOI":"10.1101\/2022.04.10.487777"},{"key":"2023072604300808000_2023.07.22.23292618v1.42","unstructured":"Fox, J.G. , The mouse in biomedical research. 2nd ed. American College of Laboratory Animal Medicine series. 2007, Amsterdam ; Boston: Elsevier, AP. v. <2-4>."},{"key":"2023072604300808000_2023.07.22.23292618v1.43","doi-asserted-by":"publisher","DOI":"10.1530\/REP-20-0422"},{"key":"2023072604300808000_2023.07.22.23292618v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(00)01801-X"},{"key":"2023072604300808000_2023.07.22.23292618v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa044"},{"key":"2023072604300808000_2023.07.22.23292618v1.46","doi-asserted-by":"publisher","DOI":"10.1530\/REP-21-0486"},{"key":"2023072604300808000_2023.07.22.23292618v1.47","doi-asserted-by":"publisher","DOI":"10.1159\/000323500"},{"key":"2023072604300808000_2023.07.22.23292618v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaq037"},{"key":"2023072604300808000_2023.07.22.23292618v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/des394"},{"key":"2023072604300808000_2023.07.22.23292618v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaq062"},{"key":"2023072604300808000_2023.07.22.23292618v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3306"},{"key":"2023072604300808000_2023.07.22.23292618v1.52","doi-asserted-by":"publisher","DOI":"10.1101\/gr.117259.110"},{"key":"2023072604300808000_2023.07.22.23292618v1.53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079667"},{"key":"2023072604300808000_2023.07.22.23292618v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2283"},{"issue":"1","key":"2023072604300808000_2023.07.22.23292618v1.55","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13073-019-0682-2","article-title":"Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores","volume":"11","year":"2019","journal-title":"Genome Med"},{"key":"2023072604300808000_2023.07.22.23292618v1.56","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-017-3767-6"},{"key":"2023072604300808000_2023.07.22.23292618v1.57","doi-asserted-by":"publisher","DOI":"10.1111\/mec.16077"},{"key":"2023072604300808000_2023.07.22.23292618v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3594"},{"key":"2023072604300808000_2023.07.22.23292618v1.59","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-014-0356-4"},{"key":"2023072604300808000_2023.07.22.23292618v1.60","doi-asserted-by":"crossref","unstructured":"Ariad, D. , et al., Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos. bioRxiv, 2023.","DOI":"10.1101\/2023.06.07.543910"},{"issue":"1","key":"2023072604300808000_2023.07.22.23292618v1.61","doi-asserted-by":"crossref","first-page":"4953","DOI":"10.1038\/s41467-022-32598-1","article-title":"Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA","volume":"13","year":"2022","journal-title":"Nat Commun"},{"issue":"1","key":"2023072604300808000_2023.07.22.23292618v1.62","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/s13073-021-00999-4","article-title":"Constructing germline research cohorts from the discarded reads of clinical tumor sequences","volume":"13","year":"2021","journal-title":"Genome Med"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.07.22.23292618","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:37:38Z","timestamp":1768505858000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.07.22.23292618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,24]]},"references-count":62,"URL":"https:\/\/doi.org\/10.1101\/2023.07.22.23292618","relation":{},"subject":[],"published":{"date-parts":[[2023,7,24]]},"subtype":"preprint"}}