{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T07:10:27Z","timestamp":1777965027383,"version":"3.51.4"},"posted":{"date-parts":[[2024,12,3]]},"group-title":"Genetic and Genomic Medicine","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Natural dizygotic twinning (DZT) results from hyper-ovulation and is considered an indicator of female fertility. DZT has low polygenicity, with only 0.20% of SNPs estimated to have a nonzero effect. A polygenic score (PGS) for DZT explains 1.6% of variance in DZT liability and we observe an odds ratio of 2.29 between the 1\n                  <jats:sup>st<\/jats:sup>\n                  and the 10\n                  <jats:sup>th<\/jats:sup>\n                  PGS decile. The PGS is higher in mothers of naturally conceived twins compared to mothers who received fertility (MAR) treatments in both the Netherlands and Norway. The largest differences were observed for mothers who received hormonal ovulation induction, indicating maternal fertility issues. A higher PGS was also linked to shorter time to pregnancy. DZT showed significant negative genetic correlations with anovulatory infertility (r\n                  <jats:sub>g<\/jats:sub>\n                  = -0.698) and PCOS (r\n                  <jats:sub>g<\/jats:sub>\n                  = -0.278), and a positive genetic correlation with endometriosis (r\n                  <jats:sub>g<\/jats:sub>\n                  = 0.279). These findings suggest DZT PGS is an important, yet under-recognized fertility marker.\n                <\/jats:p>","DOI":"10.1101\/2024.12.02.24318308","type":"posted-content","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T15:55:17Z","timestamp":1733241317000},"source":"Crossref","is-referenced-by-count":2,"title":["Polygenic Scores for Dizygotic Twinning: Insights into the Genetic Architecture of Female Fertility"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-9235","authenticated-orcid":false,"given":"Nikki","family":"Hubers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1897-3666","authenticated-orcid":false,"given":"Christian M.","family":"Page","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5579-0933","authenticated-orcid":false,"given":"Ren\u00e9","family":"Pool","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-0371","authenticated-orcid":false,"given":"Hamdi","family":"Mbarek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nils","family":"Lambalk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-9921","authenticated-orcid":false,"given":"Velja","family":"Mijatovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6570-3319","authenticated-orcid":false,"given":"Lannie","family":"Ligthart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2063-8741","authenticated-orcid":false,"given":"Jenny","family":"van Dongen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-157X","authenticated-orcid":false,"given":"Elizabeth C.","family":"Corfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey J.","family":"Beck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7865-3015","authenticated-orcid":false,"given":"Erik A.","family":"Ehli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas G.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3755-0236","authenticated-orcid":false,"given":"Gonneke","family":"Willemsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siri","family":"H\u00e5berg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer R.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5668-2368","authenticated-orcid":false,"given":"Jouke-Jan","family":"Hottenga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7099-7972","authenticated-orcid":false,"given":"Dorret I.","family":"Boomsma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025030704211121000_2024.12.02.24318308v2.1","doi-asserted-by":"crossref","unstructured":"Hall JG. Twinning. The Lancet [Internet]. 2003 Aug 30 [cited 2022 Oct 4];362(9385):735\u201343. Available from: http:\/\/www.thelancet.com\/article\/S0140673603142377\/fulltext","DOI":"10.1016\/S0140-6736(03)14237-7"},{"key":"2025030704211121000_2024.12.02.24318308v2.2","doi-asserted-by":"crossref","unstructured":"Hoekstra C , Zhao ZZ , Lambalk CB , Willemsen G , Martin NG , Boomsma DI , et al. Dizygotic twinning. Hum Reprod Update [Internet]. 2008 Jan 1 [cited 2022 Oct 4];14(1):37\u201347. Available from: https:\/\/academic.oup.com\/humupd\/article\/14\/1\/37\/827500","DOI":"10.1093\/humupd\/dmm036"},{"key":"2025030704211121000_2024.12.02.24318308v2.3","doi-asserted-by":"crossref","unstructured":"Wyshak G , White C . Genealogical study of human twinning. Am J Public Health Nations Health [Internet]. 1965 [cited 2024 Dec 2];55(10):1586\u201393. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/5890514\/","DOI":"10.2105\/AJPH.55.10.1586"},{"key":"2025030704211121000_2024.12.02.24318308v2.4","unstructured":"Bulmer MG . The Biology of Twinning in Man. Clarendon, Oxford; 1970."},{"key":"2025030704211121000_2024.12.02.24318308v2.5","doi-asserted-by":"crossref","unstructured":"Mbarek H , Steinberg S , Nyholt DR , Gordon SD , Miller MB , McRae AF , et al. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Am J Hum Genet [Internet]. 2016 May 5 [cited 2022 Oct 4];98(5):898\u2013908. Available from: http:\/\/www.cell.com\/article\/S000292971630043X\/fulltext","DOI":"10.1016\/j.ajhg.2016.03.008"},{"key":"2025030704211121000_2024.12.02.24318308v2.6","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dead247"},{"key":"2025030704211121000_2024.12.02.24318308v2.7","doi-asserted-by":"crossref","unstructured":"Duffy DL , Martin NG . The Heritability of Twinning in Seven Large Historic Pedigrees. Twin Research and Human Genetics [Internet]. 2022 Apr 20 [cited 2024 May 13];25(2):63\u20136. Available from: https:\/\/www.cambridge.org\/core\/journals\/twin-research-and-human-genetics\/article\/heritability-of-twinning-in-seven-large-historic-pedigrees\/071597E3BE6C12997EC86C8CEC097FDF","DOI":"10.1017\/thg.2022.14"},{"key":"2025030704211121000_2024.12.02.24318308v2.8","doi-asserted-by":"crossref","unstructured":"Mbarek H , Steinberg S , Nyholt DR , Gordon SD , Miller MB , McRae AF , et al. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Am J Hum Genet [Internet]. 2016 May 5 [cited 2024 Jan 17];98(5):898\u2013908. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/27132594\/","DOI":"10.1016\/j.ajhg.2016.03.008"},{"key":"2025030704211121000_2024.12.02.24318308v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/J.AJHG.2022.12.011"},{"key":"2025030704211121000_2024.12.02.24318308v2.10","unstructured":"Uffelmann E , Huang QQ , Munung NS , de Vries J , Okada Y , Martin AR , et al. Genome-wide association studies. Nature Reviews Methods Primers 2021 1:1 [Internet]. 2021 Aug 26 [cited 2025 Feb 7];1(1):1\u201321. Available from: https:\/\/www.nature.com\/articles\/s43586-021-00056-9"},{"key":"2025030704211121000_2024.12.02.24318308v2.11","unstructured":"Schipper M , de Leeuw CA , Maciel BAPC , Wightman DP , Hubers N , Boomsma DI , et al. Prioritizing effector genes at trait-associated loci using multimodal evidence. Nature Genetics 2025 [Internet]. 2025 Feb 10 [cited 2025 Feb 12];1\u201311. Available from: https:\/\/www.nature.com\/articles\/s41588-025-02084-7"},{"key":"2025030704211121000_2024.12.02.24318308v2.12","doi-asserted-by":"crossref","unstructured":"Tong S , Caddy D , Short R V . Use of dizygotic to monozygotic twinning ratio as a measure of fertility. Lancet [Internet]. 1997 Mar 22 [cited 2024 Aug 22];349(9055):843\u20135. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/9121260\/","DOI":"10.1016\/S0140-6736(96)10003-9"},{"key":"2025030704211121000_2024.12.02.24318308v2.13","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/del009"},{"key":"2025030704211121000_2024.12.02.24318308v2.14","doi-asserted-by":"crossref","unstructured":"Hoekstra C , Willemsen G , van Beijsterveldt CEMT , Lambalk CB , Montgomery GW , Boomsma DI . Body composition, smoking, and spontaneous dizygotic twinning. Fertil Steril [Internet]. 2010 Feb 1 [cited 2022 Oct 4];93(3):885\u201393. Available from: http:\/\/www.fertstert.org\/article\/S0015028208042076\/fulltext","DOI":"10.1016\/j.fertnstert.2008.10.012"},{"key":"2025030704211121000_2024.12.02.24318308v2.15","unstructured":"Hubers N , Page CM , Ligthart L , Pool R , Hottenga JJ , Van Dongen J , et al. Maternal Characteristics in Natural and Medically Assisted Reproduction Dizygotic Twin Pregnancies. Twin Res Hum Genet [Internet]. 2024 [cited 2024 Sep 18]; Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/39239778\/"},{"key":"2025030704211121000_2024.12.02.24318308v2.16","doi-asserted-by":"crossref","unstructured":"Committee of the American Society for Reproductive Medicine P. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril [Internet]. 2020 Mar 1 [cited 2024 Aug 22];113(3):533\u20135. Available from: http:\/\/www.fertstert.org\/article\/S0015028219325944\/fulltext","DOI":"10.1016\/j.fertnstert.2019.11.025"},{"key":"2025030704211121000_2024.12.02.24318308v2.17","doi-asserted-by":"crossref","unstructured":"Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril [Internet]. 2020 Mar 1 [cited 2024 Aug 7];113(3):533\u20135. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/32115183\/","DOI":"10.1016\/j.fertnstert.2019.11.025"},{"key":"2025030704211121000_2024.12.02.24318308v2.18","doi-asserted-by":"crossref","unstructured":"Van Zonneveld P , Scheffer G , Koppeschaar HPF , Fauser BCJM , Broekmans FJ , Te Velde ER . Hormone patterns after induction of ovulation with clomiphene citrate: an age-related phenomenon. Gynecol Endocrinol [Internet]. 1999 [cited 2024 May 6];13(4):259\u201365. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/10533161\/","DOI":"10.3109\/09513599909167564"},{"key":"2025030704211121000_2024.12.02.24318308v2.19","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dead197"},{"key":"2025030704211121000_2024.12.02.24318308v2.20","doi-asserted-by":"crossref","unstructured":"Dhont M . Single-embryo transfer. Semin Reprod Med [Internet]. 2001 [cited 2023 Aug 8];19(3):251\u20138. Available from: http:\/\/www.thieme-connect.com\/products\/ejournals\/html\/10.1055\/s-2001-18044","DOI":"10.1055\/s-2001-18044"},{"key":"2025030704211121000_2024.12.02.24318308v2.21","unstructured":"Vilhj\u00e1lmsson BJ , Yang J , Finucane HK , Gusev A , Lindstr\u00f6m S , Ripke S , et al. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores. Am J Hum Genet [Internet]. 2015 [cited 2022 Oct 5];97(4):576\u201392. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/26430803\/"},{"key":"2025030704211121000_2024.12.02.24318308v2.22","doi-asserted-by":"crossref","unstructured":"Bulik-Sullivan B , Loh PR , Finucane HK , Ripke S , Yang J , Patterson N , et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics 2015 47:3 [Internet]. 2015 Feb 2 [cited 2024 Aug 7];47(3):291\u20135. Available from: https:\/\/www.nature.com\/articles\/ng.3211","DOI":"10.1038\/ng.3211"},{"key":"2025030704211121000_2024.12.02.24318308v2.23","doi-asserted-by":"crossref","unstructured":"Zhang Y , Qi G , Park JH , Chatterjee N . Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nature Genetics 2018 50:9 [Internet]. 2018 Aug 13 [cited 2024 Aug 22];50(9):1318\u201326. Available from: https:\/\/www.nature.com\/articles\/s41588-018-0193-x","DOI":"10.1038\/s41588-018-0193-x"},{"key":"2025030704211121000_2024.12.02.24318308v2.24","unstructured":"Zeng J , Xue A , Jiang L , Lloyd-Jones LR , Wu Y , Wang H , et al. Widespread signatures of natural selection across human complex traits and functional genomic categories. Nature Communications 2021 12:1 [Internet]. 2021 Feb 19 [cited 2024 Sep 20];12(1):1\u201312. Available from: https:\/\/www.nature.com\/articles\/s41467-021-21446-3"},{"key":"2025030704211121000_2024.12.02.24318308v2.25","doi-asserted-by":"crossref","unstructured":"Choi SW , Mak TSH , O\u2019Reilly PF . Tutorial: a guide to performing polygenic risk score analyses. Nature Protocols 2020 15:9 [Internet]. 2020 Jul 24 [cited 2022 Oct 4];15(9):2759\u201372. Available from: https:\/\/www.nature.com\/articles\/s41596-020-0353-1","DOI":"10.1038\/s41596-020-0353-1"},{"key":"2025030704211121000_2024.12.02.24318308v2.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.07.003"},{"key":"2025030704211121000_2024.12.02.24318308v2.27","doi-asserted-by":"crossref","unstructured":"Kim Y , Lee JJ . The genetics of human fertility. Curr Opin Psychol [Internet]. 2019 Jun 1 [cited 2024 Nov 11];27:41\u20135. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/30138840\/","DOI":"10.1016\/j.copsyc.2018.07.011"},{"key":"2025030704211121000_2024.12.02.24318308v2.28","doi-asserted-by":"crossref","unstructured":"Venkatesh SS , Wittemans LBL , Palmer DS , Baya NA , Ferreira T , Hill B , et al. Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum. medRxiv [Internet]. 2024 Mar 20 [cited 2024 Jun 12]; Available from: \/pmc\/articles\/PMC10984039\/","DOI":"10.1101\/2024.03.19.24304530"},{"key":"2025030704211121000_2024.12.02.24318308v2.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)66478-1"},{"key":"2025030704211121000_2024.12.02.24318308v2.30","doi-asserted-by":"crossref","unstructured":"Beck JJ , Bruins S , Mbarek H , Davies GE , Boomsma DI. Biology and Genetics of Dizygotic and Monozygotic Twinning. Twin and Higher-order Pregnancies [Internet]. 2021 Jan 1 [cited 2023 Oct 10];31\u201350. Available from: https:\/\/link.springer.com\/chapter\/10.1007\/978-3-030-47652-6_3","DOI":"10.1007\/978-3-030-47652-6_3"},{"key":"2025030704211121000_2024.12.02.24318308v2.31","doi-asserted-by":"crossref","unstructured":"Gilfillan CP , Robertson DM , Burger HG , Leoni MA , Hurley VA , Martin NG . The control of ovulation in mothers of dizygotic twins. J Clin Endocrinol Metab [Internet]. 1996 Apr [cited 2024 Sep 19];81(4):1557\u201362. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/8636367\/","DOI":"10.1210\/jcem.81.4.8636367"},{"key":"2025030704211121000_2024.12.02.24318308v2.32","doi-asserted-by":"crossref","unstructured":"Chambers GM , Van Hoang P , Lee E , Hansen M , Sullivan EA , Bower C , et al. Hospital Costs of Multiple-Birth and Singleton-Birth Children During the First 5 Years of Life and the Role of Assisted Reproductive Technology. JAMA Pediatr [Internet]. 2014 Nov 1 [cited 2022 Oct 4];168(11):1045\u201353. Available from: https:\/\/jamanetwork.com\/journals\/jamapediatrics\/fullarticle\/1903018","DOI":"10.1001\/jamapediatrics.2014.1357"},{"key":"2025030704211121000_2024.12.02.24318308v2.33","doi-asserted-by":"crossref","unstructured":"Szymusik I , Kosinska-Kaczynska K , Bomba-Opon D , Wielgos M . IVF versus spontaneous twin pregnancies \u2013 which are at higher risk of complications? 103109\/147670582012705398 [Internet]. 2012 Dec [cited 2022 Oct 4];25(12):2725\u20138. Available from: https:\/\/www.tandfonline.com\/doi\/abs\/10.3109\/14767058.2012.705398","DOI":"10.3109\/14767058.2012.705398"},{"key":"2025030704211121000_2024.12.02.24318308v2.34","doi-asserted-by":"crossref","unstructured":"Santana DS , Silveira C , Costa ML , Souza RT , Surita FG , Souza JP , et al. Perinatal outcomes in twin pregnancies complicated by maternal morbidity: Evidence from the WHO Multicountry Survey on Maternal and Newborn Health. BMC Pregnancy Childbirth [Internet]. 2018 Nov 20 [cited 2024 Dec 2];18(1):1\u201311. Available from: https:\/\/bmcpregnancychildbirth.biomedcentral.com\/articles\/10.1186\/s12884-018-2082-9","DOI":"10.1186\/s12884-018-2082-9"},{"key":"2025030704211121000_2024.12.02.24318308v2.35","doi-asserted-by":"crossref","unstructured":"Black M , Bhattacharya S . Epidemiology of multiple pregnancy and the effect of assisted conception. Semin Fetal Neonatal Med [Internet]. 2010 [cited 2024 Jun 12];15(6):306\u201312. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/20630816\/","DOI":"10.1016\/j.siny.2010.06.004"},{"key":"2025030704211121000_2024.12.02.24318308v2.36","doi-asserted-by":"crossref","unstructured":"Lambalk CB . Is there a role for follicle-stimulating-hormone receptor in familial dizygotic twinning? Lancet [Internet]. 2001 Mar 10 [cited 2024 Sep 19];357(9258):735\u20136. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/11253961\/","DOI":"10.1016\/S0140-6736(00)04178-7"},{"key":"2025030704211121000_2024.12.02.24318308v2.37","doi-asserted-by":"crossref","unstructured":"Doody KJ . Infertility Treatment Now and in the Future. Obstet Gynecol Clin North Am [Internet]. 2021 Dec 1 [cited 2022 Oct 4];48(4):801\u201312. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/34756298\/","DOI":"10.1016\/j.ogc.2021.07.005"},{"key":"2025030704211121000_2024.12.02.24318308v2.38","doi-asserted-by":"crossref","unstructured":"Farland L V. , Stern JE , Liu C ling, Cabral HJ, Coddington CC, Diop H, et al. Pregnancy outcomes among women with endometriosis and fibroids: registry linkage study in Massachusetts. Am J Obstet Gynecol [Internet]. 2022 Jun 1 [cited 2024 Sep 18];226(6):829.e1-829.e14. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/35108504\/","DOI":"10.1016\/j.ajog.2021.12.268"},{"key":"2025030704211121000_2024.12.02.24318308v2.39","doi-asserted-by":"crossref","unstructured":"Kiewa J , Mortlock S , Meltzer-Brody S , Middeldorp C , Wray NR , Byrne EM . A Common Genetic Factor Underlies Genetic Risk for Gynaecological and Reproductive Disorders and Is Correlated with Risk to Depression. Neuroendocrinology [Internet]. 2023 Oct 1 [cited 2024 Sep 19];113(10):1059\u201375. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/37544299\/","DOI":"10.1159\/000533413"},{"key":"2025030704211121000_2024.12.02.24318308v2.40","doi-asserted-by":"crossref","unstructured":"Rahmioglu N , Mortlock S , Ghiasi M , M\u00f8ller PL , Stefansdottir L , Galarneau G , et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet [Internet]. 2023 Mar 1 [cited 2024 Aug 7];55(3):423\u201336. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/36914876\/","DOI":"10.1038\/s41588-023-01323-z"},{"key":"2025030704211121000_2024.12.02.24318308v2.41","unstructured":"Day F , Karaderi T , Jones MR , Meun C , He C , Drong A , et al. Large-scale genome-wide meta- analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet [Internet]. 2018 Dec 1 [cited 2024 Aug 7];14(12). Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/30566500\/"},{"key":"2025030704211121000_2024.12.02.24318308v2.42","doi-asserted-by":"crossref","unstructured":"Lyle SM , Ahmed S , Elliott JE , Stener-Victorin E , Nachtigal MW , Dr\u00f6gem\u00f6ller BI . Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome. J Hum Genet [Internet]. 2023 May 1 [cited 2024 Sep 19];68(5):347\u201353. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/36720993\/","DOI":"10.1038\/s10038-023-01120-w"},{"key":"2025030704211121000_2024.12.02.24318308v2.43","doi-asserted-by":"crossref","unstructured":"Benonisdottir S , Straub VJ , Kong A , Mills MC . Genetics of female and male reproductive traits and their relationship with health, longevity and consequences for offspring. Nature Aging 2024 4:12 [Internet]. 2024 Dec 13 [cited 2025 Feb 5];4(12):1745\u201359. Available from: https:\/\/www.nature.com\/articles\/s43587-024-00733-w","DOI":"10.1038\/s43587-024-00733-w"},{"key":"2025030704211121000_2024.12.02.24318308v2.44","unstructured":"Ragione AD , Ross CT , Redhead D. A gene\u2013culture co-evolutionary perspective on the puzzle of human twinship. Evol Hum Sci [Internet]. 2024 Nov 11 [cited 2024 Nov 14];6:e47. Available from: https:\/\/www.cambridge.org\/core\/journals\/evolutionary-human-sciences\/article\/geneculture-coevolutionary-perspective-on-the-puzzle-of-human-twinship\/E81184315552107BF5D2C203052B7F30"},{"key":"2025030704211121000_2024.12.02.24318308v2.45","doi-asserted-by":"crossref","unstructured":"Nylander PPS . The Factors That Influence Twinning Rates. Acta geneticae medicae et gemellologiae: twin research [Internet]. 1981 [cited 2024 Nov 14];30(3):189\u2013202. Available from: https:\/\/www.cambridge.org\/core\/journals\/amg-acta-geneticae-medicae-et-gemellologiae-twin-research\/article\/factors-that-influence-twinning-rates\/99A3A11AE144956B7FEDD27C4F7B74F6","DOI":"10.1017\/S0001566000007650"},{"key":"2025030704211121000_2024.12.02.24318308v2.46","doi-asserted-by":"crossref","unstructured":"Ligthart L , Van Beijsterveldt CEM , Kevenaar ST , De Zeeuw E , Van Bergen E , Bruins S , et al. The Netherlands Twin Register: Longitudinal Research Based on Twin and Twin-Family Designs. Twin Research and Human Genetics [Internet]. 2019 Dec 1 [cited 2022 Oct 4];22(6):623\u201336. Available from: https:\/\/www.cambridge.org\/core\/journals\/twin-research-and-human-genetics\/article\/netherlands-twin-register-longitudinal-research-based-on-twin-and-twinfamily-designs\/C68488FDD92716CB9ED7C040B9776E2F","DOI":"10.1017\/thg.2019.93"},{"key":"2025030704211121000_2024.12.02.24318308v2.47","doi-asserted-by":"crossref","unstructured":"Boomsma DI , Orlebeke JF , van Baal GCM . The Dutch Twin Register: growth data on weight and height. Behav Genet [Internet]. 1992 Mar [cited 2023 Dec 5];22(2):247\u201351. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/1596264\/","DOI":"10.1007\/BF01067004"},{"key":"2025030704211121000_2024.12.02.24318308v2.48","doi-asserted-by":"crossref","unstructured":"Horwitz TB , Balbona J V. , Paulich KN , Keller MC . Evidence of correlations between human partners based on systematic reviews and meta-analyses of 22 traits and UK Biobank analysis of 133 traits. Nat Hum Behav [Internet]. 2023 Sep 1 [cited 2025 Feb 5];7(9):1568. Available from: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC10967253\/","DOI":"10.1038\/s41562-023-01672-z"},{"key":"2025030704211121000_2024.12.02.24318308v2.49","unstructured":"ClomiPHENE Monograph for Professionals - Drugs.com [Internet]. [cited 2023 Oct 13]. Available from: https:\/\/www.drugs.com\/monograph\/clomiphene.html"},{"key":"2025030704211121000_2024.12.02.24318308v2.50","doi-asserted-by":"crossref","unstructured":"Magnus P , Birke C , Vejrup K , Haugan A , Alsaker E , Daltveit AK , et al. Cohort Profile Update: The Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol [Internet]. 2016 Apr 11 [cited 2023 Aug 14];45(2):382\u20138. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/27063603\/","DOI":"10.1093\/ije\/dyw029"},{"key":"2025030704211121000_2024.12.02.24318308v2.51","doi-asserted-by":"crossref","unstructured":"Paltiel L , Haugan A , Skjerden T , Harbak K , B\u00e6kken S , Stensrud NK , et al. The biobank of the Norwegian Mother and Child Cohort Study \u2013 present status. Norsk Epidemiologi [Internet]. 2014 Dec 22 [cited 2024 Jul 6];24(1\u20132):29\u201335. Available from: https:\/\/www.ntnu.no\/ojs\/index.php\/norepid\/article\/view\/1755","DOI":"10.5324\/nje.v24i1-2.1755"},{"key":"2025030704211121000_2024.12.02.24318308v2.52","doi-asserted-by":"crossref","unstructured":"Irgens LM . The Medical Birth Registry of Norway; a source for epidemiological and clinical research. Scand J Rheumatol Suppl [Internet]. 1998 [cited 2024 Jun 12];107(107):105\u20138. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/9759145\/","DOI":"10.1080\/03009742.1998.11720780"},{"key":"2025030704211121000_2024.12.02.24318308v2.53","doi-asserted-by":"crossref","unstructured":"Zeng J , De Vlaming R , Wu Y , Robinson MR , Lloyd-Jones LR , Yengo L , et al. Signatures of negative selection in the genetic architecture of human complex traits. Nat Genet [Internet]. 2018 May 1 [cited 2022 Oct 5];50(5):746\u201353. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/29662166\/","DOI":"10.1038\/s41588-018-0101-4"},{"key":"2025030704211121000_2024.12.02.24318308v2.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.02.002"},{"key":"2025030704211121000_2024.12.02.24318308v2.55","doi-asserted-by":"crossref","unstructured":"Bulik-Sullivan B , Finucane HK , Anttila V , Gusev A , Day FR , Loh PR , et al. An atlas of genetic correlations across human diseases and traits. Nature Genetics 2015 47:11 [Internet]. 2015 Sep 28 [cited 2024 Aug 7];47(11):1236\u201341. Available from: https:\/\/www.nature.com\/articles\/ng.3406","DOI":"10.1038\/ng.3406"},{"key":"2025030704211121000_2024.12.02.24318308v2.56","doi-asserted-by":"crossref","unstructured":"Mathieson I , Day FR , Barban N , Tropf FC , Brazel DM , van Heemst D , et al. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nat Hum Behav [Internet]. 2023 May 1 [cited 2024 Aug 7];7(5):790\u2013801. Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/36864135\/","DOI":"10.1038\/s41562-023-01528-6"},{"key":"2025030704211121000_2024.12.02.24318308v2.57","unstructured":"Laisk T , Soares ALG , Ferreira T , Painter JN , Censin JC , Laber S , et al. The genetic architecture of sporadic and multiple consecutive miscarriage. Nature Communications 2020 11:1 [Internet]. 2020 Nov 25 [cited 2024 Sep 13];11(1):1\u201312. Available from: https:\/\/www.nature.com\/articles\/s41467-020-19742-5"},{"key":"2025030704211121000_2024.12.02.24318308v2.58","unstructured":"Cerv\u00e1n-Mart\u00edn M , T\u00fcttelmann F , Lopes AM , Bossini-Castillo L , Rivera-Egea R , Garrido N , et al. Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility. Communications Biology 2022 5:1 [Internet]. 2022 Nov 10 [cited 2024 Aug 7];5(1):1\u201313. Available from: https:\/\/www.nature.com\/articles\/s42003-022-04192-0"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.12.02.24318308","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:21:52Z","timestamp":1768508512000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.12.02.24318308"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,3]]},"references-count":58,"URL":"https:\/\/doi.org\/10.1101\/2024.12.02.24318308","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1007\/s10815-025-03515-4","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,12,3]]},"subtype":"preprint"}}