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1. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Author

Mathieson, Iain, Day, Felix R, Barban, Nicola, Tropf, Felix C, Brazel, David M, EQTLGen Consortium, BIOS Consortium, Vaez, Ahmad, Van Zuydam, Natalie, Bitarello, Bárbara D, Gardner, Eugene J, Akimova, Evelina T, Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F, Boomsma, Dorret I, Bosak, Kristina, Brumat, Marco, Buring, Julie E, Cesarini, David, Chasman, Daniel I, Chavarro, Jorge E, Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J, Esko, Tõnu, Faul, Jessica D, FinnGen Study, Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J, Gelemanovic, Andrea, De Geus, Eco JC, Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P, Hayward, Caroline, He, Chunyan, Van Heemst, Diana, Hill, W David, Hoffmann, Eva R, Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon LR, Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lifelines Cohort Study, Lind, Penelope A, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik KE, Mahajan, Anubha, Martin, Nicholas G, Mbarek, Hamdi, McCarthy, Mark I, McMahon, George, Medland, Sarah E, Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A, Mitchell, Paul, Møllegaard, Stine, Mook-Kanamori, Dennis O, Morgan, Anna, Van Der Most, Peter J, De Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M, Noordam, Raymond, Penninx, Brenda WJH, Peters, Annette, Peyser, Patricia A, Polašek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W, Ridker, Paul M, Rietveld, Cornelius A, Ring, Susan M, Rose, Lynda M, Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A, Stankovic, Stasa, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A, Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A Roy, Timpson, Nicholas J, Turman, Constance, Uitterlinden, André G, Waldenberger, Melanie, Wareham, Nicholas J, Weir, David R, Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, Den Hoed, Marcel, Ong, Ken K, Mills, Melinda C, Perry, John RB, Mathieson, Iain [0000-0002-4256-3982], Day, Felix R [0000-0003-3789-7651], Vaez, Ahmad [0000-0001-9048-3795], Bitarello, Bárbara D [0000-0001-7676-9367], Gardner, Eugene J [0000-0001-9671-1533], Akimova, Evelina T [0000-0001-8733-3745], Bergmann, Sven [0000-0002-6785-9034], Bielak, Lawrence F [0000-0002-3443-8030], Boomsma, Dorret I [0000-0002-7099-7972], Chasman, Daniel I [0000-0003-3357-0862], Chavarro, Jorge E [0000-0002-4436-9630], Cocca, Massimiliano [0000-0002-1127-7596], Concas, Maria Pina [0000-0003-3598-2537], Davey Smith, George [0000-0002-1407-8314], Davies, Gail [0000-0003-1120-7026], Franco, Oscar [0000-0002-4606-4929], Ganna, Andrea [0000-0002-8147-240X], Gaskins, Audrey J [0000-0001-9195-646X], Gieger, Christian [0000-0001-6986-9554], Girotto, Giorgia [0000-0003-4507-6589], Grabe, Hans Jörgen [0000-0003-3684-4208], Gunderson, Erica P [0000-0002-2039-1964], He, Chunyan [0000-0001-9443-4368], Hoffmann, Eva R [0000-0002-2588-0652], Homuth, Georg [0000-0001-6839-0605], Hottenga, Jouke Jan [0000-0002-5668-2368], Hyppӧnen, Elina [0000-0003-3670-9399], Ikram, M Arfan [0000-0003-0372-8585], Jansen, Rick [0000-0002-3333-6737], Johannesson, Magnus [0000-0001-8759-6393], Kamali, Zoha [0000-0001-6492-5887], Kavousi, Maryam [0000-0001-5976-6519], Kifley, Annette [0000-0002-3764-4905], Kiiskinen, Tuomo [0000-0002-6306-8227], Kraft, Peter [0000-0002-4472-8103], Langenberg, Claudia [0000-0002-5017-7344], Lind, Penelope A [0000-0002-3887-2598], Luan, Jian'an [0000-0003-3137-6337], Magnusson, Patrik KE [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mbarek, Hamdi [0000-0002-1108-0371], Metspalu, Andres [0000-0002-3718-796X], Milani, Lili [0000-0002-5323-3102], Møllegaard, Stine [0000-0001-5676-2248], Morgan, Anna [0000-0001-6290-445X], van der Most, Peter J [0000-0001-8450-3518], Nauck, Matthias [0000-0002-6678-7964], Nolte, Ilja M [0000-0001-5047-4077], Noordam, Raymond [0000-0001-7801-809X], Peters, Annette [0000-0001-6645-0985], Peyser, Patricia A [0000-0002-9717-8459], Pribisalic, Ajka [0000-0002-3725-3728], Rietveld, Cornelius A [0000-0003-4053-1861], Ring, Susan M [0000-0003-3103-9330], Smith, Jennifer A [0000-0002-3575-5468], Stankovic, Stasa [0000-0002-6602-1379], Teumer, Alexander [0000-0002-8309-094X], Thurik, A Roy [0000-0002-0242-6908], Timpson, Nicholas J [0000-0002-7141-9189], Uitterlinden, André G [0000-0002-7276-3387], Waldenberger, Melanie [0000-0003-0583-5093], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Zhao, Wei [0000-0001-7388-0692], Zhao, Yajie [0000-0002-2747-0219], Snieder, Harold [0000-0003-1949-2298], den Hoed, Marcel [0000-0001-8081-428X], Ong, Ken K [0000-0003-4689-7530], Mills, Melinda C [0000-0003-1704-0001], Perry, John RB [0000-0001-6483-3771], and Apollo - University of Cambridge Repository

Subjects
Aging, Fertility, Reproduction, Humans, Female, Menopause, Selection, Genetic, FOS: Medical biotechnology, Child
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.

Published
2023

2. Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure

Author

Oelen, Roy, de Vries, Dylan H, Brugge, Harm, Gordon, M Grace, Vochteloo, Martijn, single-cell eQTLGen consortium, BIOS Consortium, Ye, Chun J, Westra, Harm-Jan, Franke, Lude, and van der Wijst, Monique GP

Subjects
Lupus Erythematosus, C-Type, Mitogen, Inflammatory and immune system, Mononuclear, Systemic, Human Genome, Gene Expression Regulation, Lectins, Receptors, Leukocytes, Genetics, Humans, RNA, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, BIOS Consortium, Aetiology, single-cell eQTLGen consortium, Infection, Signal Transduction, Biotechnology
Abstract

The host's gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host's genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.

Published
2022

3. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Author

Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Mills, Melinda C [0000-0003-1704-0001], Tropf, Felix C [0000-0003-2445-515X], Brazel, David M [0000-0001-5361-2498], Vaez, Ahmad [0000-0001-9048-3795], Pers, Tune H [0000-0003-0207-4831], Snieder, Harold [0000-0003-1949-2298], Perry, John RB [0000-0001-6483-3771], Ong, Ken K [0000-0003-4689-7530], den Hoed, Marcel [0000-0001-8081-428X], Barban, Nicola [0000-0002-4362-4652], Day, Felix R [0000-0003-3789-7651], and Apollo - University of Cambridge Repository

Subjects
Male, Adolescent, Reproduction, Age Factors, Coitus, Parturition, Humans, Female, Polymorphism, Single Nucleotide, Genetic Association Studies
Abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Published
2021

4. Genetic predisposition to mosaic Y chromosome loss in blood

Author

Thompson, Deborah J, Genovese, Giulio, Halvardson, Jonatan, Ulirsch, Jacob C, Wright, Daniel J, Terao, Chikashi, Davidsson, Olafur B, Day, Felix R, Sulem, Patrick, Jiang, Yunxuan, Danielsson, Marcus, Davies, Hanna, Dennis, Joe, Dunlop, Malcolm G, Easton, Douglas F, Fisher, Victoria A, Zink, Florian, Houlston, Richard S, Ingelsson, Martin, Kar, Siddhartha, Kerrison, Nicola D, Kinnersley, Ben, Kristjansson, Ragnar P, Law, Philip J, Li, Rong, Loveday, Chey, Mattisson, Jonas, McCarroll, Steven A, Murakami, Yoshinori, Murray, Anna, Olszewski, Pawel, Rychlicka-Buniowska, Edyta, Scott, Robert A, Thorsteinsdottir, Unnur, Tomlinson, Ian, Moghadam, Behrooz Torabi, Turnbull, Clare, Wareham, Nicholas J, Gudbjartsson, Daniel F, International Lung Cancer Consortium (INTEGRAL-ILCCO), Breast Cancer Association Consortium, Consortium Of Investigators Of Modifiers Of BRCA1/2, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, Prostate Cancer Association Group To Investigate Cancer Associated Alterations In The Genome (PRACTICAL) Consortium, Kidney Cancer GWAS Meta-Analysis Project, EQTLGen Consortium, Biobank-Based Integrative Omics Study (BIOS) Consortium, 23andMe Research Team, Kamatani, Yoichiro, Hoffmann, Eva R, Jackson, Steve P, Stefansson, Kari, Auton, Adam, Ong, Ken K, Machiela, Mitchell J, Loh, Po-Ru, Dumanski, Jan P, Chanock, Stephen J, Forsberg, Lars A, Perry, John RB, Thompson, Deborah [0000-0003-1465-5799], Wright, Daniel [0000-0003-3983-2093], Day, Felix [0000-0003-3789-7651], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Wareham, Nicholas [0000-0003-1422-2993], Jackson, Stephen [0000-0001-9317-7937], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], and Apollo - University of Cambridge Repository

Subjects
Adult, Genetic Markers, Male, 0303 health sciences, Chromosomes, Human, Y, Mosaicism, Computational Biology, Middle Aged, Genomic Instability, United Kingdom, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Neoplasms, Databases, Genetic, Leukocytes, Humans, Female, Genetic Predisposition to Disease, Chromosome Deletion, 030304 developmental biology, Aged
Abstract

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Published
2019
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5. Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Author

Paul RHJ Timmers, Ninon Mounier, Kristi Läll, Krista Fischer, Zheng Ning, Xiao Feng, Andrew Bretherick, David W Clark, eQTLGen Consortium, Xia Shen, Tōnu Esko, Zoltán Kutalik, James F Wilson, and Peter K Joshi

Subjects
Genetics, Dorsolateral prefrontal cortex, medicine.anatomical_structure, ABO blood group system, medicine, GADD45G, Cancer, Dementia, Genomics, Disease, Biology, medicine.disease, Gene
Abstract

We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer –but not other cancers-explain the most variance, possibly reflecting modern susceptibilities, whilst cancer may act through many rare variants, or the environment. Resultant polygenic scores predict a mean lifespan difference of around five years of life across the deciles.

Published
2018

6. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Author

Mills, Melinda C, Tropf, Felix C, Brazel, David M, Van Zuydam, Natalie, Vaez, Ahmad, EQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, Den Hoed, Marcel, Barban, Nicola, and Day, Felix R

Subjects
Male, Adolescent, Reproduction, Age Factors, Coitus, Parturition, Humans, Female, FOS: Medical biotechnology, Polymorphism, Single Nucleotide, Genetic Association Studies, 3. Good health
Abstract

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

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