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"2023-05-00", "journal": {"title": "Nat Hum Behav", "issn": "2397-3374", "volume": "7", "issue": "5", "pages": "790-801", "issn-l": null}, "abstract": "Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.", "doi": "10.1038/s41562-023-01528-6", "pmid": "36864135", "labels": [], "xrefs": [{"db": "pii", "key": "10.1038/s41562-023-01528-6"}], "notes": [], "created": "2026-09-23T08:38:43.054Z", "modified": "2026-09-23T08:38:44.809Z"}, {"entity": "publication", "iuid": "ab0120159cb947bfb2d589e1046e0646", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ab0120159cb947bfb2d589e1046e0646.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ab0120159cb947bfb2d589e1046e0646"}}, "title": "Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.", "authors": [{"family": "Tin", "given": "Adrienne", "initials": "A", "orcid": "0000-0002-4207-5866", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d0c7ca063aad427da7db8a96ea1937da.json"}}, 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"orcid": "0000-0002-4059-1779", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5283e0dd4ad745938042b3fb48fcb73d.json"}}, {"family": "Heid", "given": "Iris M", "initials": "IM"}, {"family": "Hung", "given": "Adriana M", "initials": "AM", "orcid": "0000-0002-3203-1608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c9c6d7e42fd4f1bb64e93c1660a6010.json"}}, {"family": "Teumer", "given": "Alexander", "initials": "A"}, {"family": "Pattaro", "given": "Cristian", "initials": "C"}, {"family": "Woodward", "given": "Owen M", "initials": "OM", "orcid": "0000-0001-9514-2180", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/387efd5abfac4fd9b8114a3b1da7fb75.json"}}, {"family": "Vitart", "given": "Veronique", "initials": "V", "orcid": "0000-0002-4991-3797", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3270297f0f1b4de4bb181d7be8e1f447.json"}}, {"family": "K\u00f6ttgen", "given": "Anna", "initials": "A", "orcid": "0000-0002-4671-3714", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ed83f5aa153f40169b9975b5c4360653.json"}}], "type": "journal article", "published": "2019-10-00", "journal": {"title": "Nat. Genet.", "issn": "1546-1718", "volume": "51", "issue": "10", "pages": "1459-1474", "issn-l": "1061-4036"}, "abstract": "Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.", "doi": "10.1038/s41588-019-0504-x", "pmid": "31578528", "labels": [], "xrefs": [{"db": "mid", "key": "NIHMS1538428"}, {"db": "pmc", "key": "PMC6858555"}, {"db": "pii", "key": "10.1038/s41588-019-0504-x"}], "notes": [], "created": "2026-09-23T06:33:58.552Z", "modified": "2026-09-23T06:33:59.410Z"}, {"entity": "publication", "iuid": "e3153b7609ad4515bbdda959618c46ed", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e3153b7609ad4515bbdda959618c46ed.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e3153b7609ad4515bbdda959618c46ed"}}, "title": "A catalog of genetic loci associated with kidney function from analyses of a million individuals.", "authors": [{"family": "Wuttke", "given": "Matthias", "initials": "M", "orcid": "0000-0003-3420-5082", "researcher": 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"Snieder", "given": "Harold", "initials": "H"}, {"family": "Stefansson", "given": "Kari", "initials": "K", "orcid": "0000-0003-1676-864X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9edf80871ac84e76a4d1316fc7079d7d.json"}}, {"family": "Hung", "given": "Adriana M", "initials": "AM", "orcid": "0000-0002-3203-1608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8c9c6d7e42fd4f1bb64e93c1660a6010.json"}}, {"family": "Heid", "given": "Iris M", "initials": "IM"}, {"family": "Scholz", "given": "Markus", "initials": "M", "orcid": "0000-0002-4059-1779", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5283e0dd4ad745938042b3fb48fcb73d.json"}}, {"family": "Teumer", "given": "Alexander", "initials": "A", "orcid": "0000-0002-8309-094X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1a40a959d1b8480cb8268e00f77a0449.json"}}, {"family": "K\u00f6ttgen", "given": "Anna", "initials": "A", "orcid": "0000-0002-4671-3714", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ed83f5aa153f40169b9975b5c4360653.json"}}, {"family": "Pattaro", "given": "Cristian", "initials": "C", "orcid": "0000-0002-4119-0109", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d8c7ff447060429da7904b26ea8b1d4b.json"}}], "type": "journal article", "published": "2019-06-00", "journal": {"title": "Nat. Genet.", "issn": "1546-1718", "volume": "51", "issue": "6", "pages": "957-972", "issn-l": "1061-4036"}, "abstract": "Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.", "doi": "10.1038/s41588-019-0407-x", "pmid": "31152163", "labels": [], "xrefs": [{"db": "mid", "key": "NIHMS1038587"}, {"db": "pmc", "key": "PMC6698888"}, {"db": "pii", "key": "10.1038/s41588-019-0407-x"}], "notes": [], "created": "2026-09-22T19:59:34.302Z", "modified": "2026-09-22T19:59:35.870Z"}, {"entity": "publication", "iuid": "a47af805c5644d568e267461ae8e9f42", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a47af805c5644d568e267461ae8e9f42.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a47af805c5644d568e267461ae8e9f42"}}, "title": "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.", "authors": [{"family": "Justice", "given": "Anne E", "initials": "AE"}, {"family": "Karaderi", "given": "Tugce", "initials": "T"}, {"family": "Highland", 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"initials": "RJF", "orcid": "0000-0002-8532-5087", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/179eb6511eba4d33b633599c5652e344.json"}}, {"family": "North", "given": "Kari E", "initials": "KE"}, {"family": "Lindgren", "given": "Cecilia M", "initials": "CM", "orcid": "0000-0002-4903-9374", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b5c82df5e7bc43e4874726fb16924cf5.json"}}, {"family": "CHD Exome+ Consortium", "given": "", "initials": ""}, {"family": "Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium", "given": "", "initials": ""}, {"family": "EPIC-CVD Consortium", "given": "", "initials": ""}, {"family": "ExomeBP Consortium", "given": "", "initials": ""}, {"family": "Global Lipids Genetic Consortium", "given": "", "initials": ""}, {"family": "GoT2D Genes Consortium", "given": "", "initials": ""}, {"family": "InterAct", "given": "", "initials": ""}, {"family": "ReproGen Consortium", "given": "", "initials": ""}, {"family": "T2D-Genes Consortium", "given": "", "initials": ""}, {"family": "MAGIC Investigators", "given": "", "initials": ""}], "type": "journal article", "published": "2019-03-00", "journal": {"title": "Nat. Genet.", "issn": "1546-1718", "volume": "51", "issue": "3", "pages": "452-469", "issn-l": "1061-4036"}, "abstract": "Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF \u22655%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.", "doi": "10.1038/s41588-018-0334-2", "pmid": "30778226", "labels": [], "xrefs": [{"db": "mid", "key": "NIHMS1016010"}, {"db": "pmc", "key": "PMC6560635"}, {"db": "pii", "key": "10.1038/s41588-018-0334-2"}], "notes": [], "created": "2026-09-23T07:38:33.413Z", "modified": "2026-09-23T07:38:34.499Z"}, {"entity": "publication", "iuid": "3319ed3faaa04b37904ac096febd0936", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3319ed3faaa04b37904ac096febd0936.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3319ed3faaa04b37904ac096febd0936"}}, "title": "Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.", "authors": [{"family": "Justice", "given": "Anne E", "initials": "AE", "orcid": "0000-0002-8903-8712", "researcher": 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"https://publications-affiliated.scilifelab.se/researcher/f8b84ab3a8e94c5f9f9668e5550f6ace.json"}}, {"family": "Balkau", "given": "Beverley", "initials": "B"}, {"family": "Bandinelli", "given": "Stefania", "initials": "S"}, {"family": "B\u00f6ger", "given": "Carsten A", "initials": "CA"}, {"family": "Boomsma", "given": "Dorret I", "initials": "DI"}, {"family": "Bouchard", "given": "Claude", "initials": "C"}, {"family": "Bruinenberg", "given": "Marcel", "initials": "M"}, {"family": "Chasman", "given": "Daniel I", "initials": "DI"}, {"family": "Chen", "given": "Yii-DerIda", "initials": "YD"}, {"family": "Chines", "given": "Peter S", "initials": "PS"}, {"family": "Cooper", "given": "Richard S", "initials": "RS"}, {"family": "Cucca", "given": "Francesco", "initials": "F"}, {"family": "Cusi", "given": "Daniele", "initials": "D"}, {"family": "Faire", "given": "Ulf de", "initials": "U"}, {"family": "Ferrucci", "given": "Luigi", "initials": "L"}, {"family": "Franks", "given": "Paul W", "initials": "PW"}, {"family": "Froguel", "given": "Philippe", "initials": "P"}, {"family": "Gordon-Larsen", "given": "Penny", "initials": "P", "orcid": "0000-0001-5322-4188", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/480fa70683fb44a0bda6b322a1d36439.json"}}, {"family": "Grabe", "given": "Hans-J\u00f6rgen", "initials": "HJ"}, {"family": "Gudnason", "given": "Vilmundur", "initials": "V"}, {"family": "Haiman", "given": "Christopher A", "initials": "CA"}, {"family": "Hayward", "given": "Caroline", "initials": "C"}, {"family": "Hveem", "given": "Kristian", "initials": "K"}, {"family": "Johnson", "given": "Andrew D", "initials": "AD"}, {"family": "Wouter Jukema", "given": "J", "initials": "J", "orcid": "0000-0002-3246-8359", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/51be7e89ccfd4bbe93b216028c57a376.json"}}, {"family": "Kardia", "given": "Sharon L R", "initials": "SLR"}, {"family": "Kivimaki", "given": "Mika", "initials": "M", "orcid": "0000-0002-4699-5627", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/59d7f4b1a8f8464eba40b0abe733aae9.json"}}, {"family": "Kooner", "given": "Jaspal S", "initials": "JS"}, {"family": "Kuh", "given": "Diana", "initials": "D"}, {"family": "Laakso", "given": "Markku", "initials": "M"}, {"family": "Lehtim\u00e4ki", "given": "Terho", "initials": "T"}, {"family": "Marchand", "given": "Loic Le", "initials": "LL"}, {"family": "M\u00e4rz", "given": "Winfried", "initials": "W"}, {"family": "McCarthy", "given": "Mark I", "initials": "MI"}, {"family": "Metspalu", "given": "Andres", "initials": "A"}, {"family": "Morris", "given": "Andrew P", "initials": "AP"}, {"family": "Ohlsson", "given": "Claes", "initials": "C"}, {"family": "Palmer", "given": "Lyle J", "initials": "LJ"}, {"family": "Pasterkamp", "given": "Gerard", "initials": "G"}, {"family": "Pedersen", "given": "Oluf", "initials": "O"}, {"family": "Peters", "given": "Annette", "initials": "A"}, {"family": "Peters", "given": "Ulrike", "initials": "U"}, {"family": "Polasek", "given": "Ozren", "initials": "O"}, {"family": "Psaty", "given": "Bruce M", "initials": "BM"}, {"family": "Qi", "given": "Lu", "initials": "L"}, {"family": "Rauramaa", "given": "Rainer", "initials": "R"}, {"family": "Smith", "given": "Blair H", "initials": "BH", "orcid": "0000-0002-5362-9430", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5f30912f5a8e443eac572814f3990d7f.json"}}, {"family": "S\u00f8rensen", "given": "Thorkild I A", "initials": "TIA"}, {"family": "Strauch", "given": "Konstantin", "initials": "K"}, {"family": "Tiemeier", "given": "Henning", "initials": "H", "orcid": "0000-0002-4395-1397", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bed764abb33d4d9e8bcd05dd64379a7c.json"}}, {"family": "Tremoli", "given": "Elena", "initials": "E"}, {"family": "van der Harst", "given": "Pim", "initials": "P"}, {"family": "Vestergaard", "given": "Henrik", "initials": "H", "orcid": "0000-0003-3090-269X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e2fa5c4f74894d6a833afd105ec72848.json"}}, {"family": "Vollenweider", "given": "Peter", "initials": "P"}, {"family": "Wareham", "given": "Nicholas J", "initials": "NJ"}, {"family": "Weir", "given": "David R", "initials": "DR"}, {"family": "Whitfield", "given": "John B", "initials": "JB"}, {"family": "Wilson", "given": "James F", "initials": "JF", "orcid": "0000-0001-5751-9178", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/513b6983cc9d478ab9d81c2f21579961.json"}}, {"family": "Tyrrell", "given": "Jessica", "initials": "J"}, {"family": "Frayling", "given": "Timothy M", "initials": "TM"}, {"family": "Barroso", "given": "In\u00eas", "initials": "I"}, {"family": "Boehnke", "given": "Michael", "initials": "M"}, {"family": "Deloukas", "given": "Panagiotis", "initials": "P"}, {"family": "Fox", "given": "Caroline S", "initials": "CS"}, {"family": "Hirschhorn", "given": "Joel N", "initials": "JN"}, {"family": "Hunter", "given": "David J", "initials": "DJ"}, {"family": "Spector", "given": "Tim D", "initials": "TD"}, {"family": "Strachan", "given": "David P", "initials": "DP", "orcid": "0000-0001-7854-1366", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d43385a350914b0a843fb49008d108b0.json"}}, {"family": "van Duijn", "given": "Cornelia M", "initials": "CM"}, {"family": "Heid", "given": "Iris M", "initials": "IM"}, {"family": "Mohlke", "given": "Karen L", "initials": "KL", "orcid": "0000-0001-6721-153X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fac0e041c56347fe98cef9ae8f004b67.json"}}, {"family": "Marchini", "given": "Jonathan", "initials": "J", "orcid": "0000-0003-0610-8322", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a7d0d3e23a76434098fa7731ac294cd1.json"}}, {"family": "Loos", "given": "Ruth J F", "initials": "RJF"}, {"family": "Kilpel\u00e4inen", "given": "Tuomas O", "initials": "TO"}, {"family": "Liu", "given": "Ching-Ti", "initials": "CT", "orcid": "0000-0002-0703-0742", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0df836bc876845a6af66828561f24a27.json"}}, {"family": "Borecki", "given": "Ingrid B", "initials": "IB"}, {"family": "North", "given": "Kari E", "initials": "KE"}, {"family": "Cupples", "given": "L Adrienne", "initials": "LA"}], "type": "journal article", "published": "2017-04-26", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "8", "issue": null, "pages": "14977", "issn-l": "2041-1723"}, "abstract": "Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.", "doi": "10.1038/ncomms14977", "pmid": "28443625", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC5414044"}, {"db": "pii", "key": "ncomms14977"}], "notes": [], "created": "2018-12-05T09:47:57.139Z", "modified": "2026-09-23T06:42:25.568Z"}]}