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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. Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales

Author

Knight, Rochelle, Walker, Venexia, Ip, Samantha, Cooper, Jennifer A, Bolton, Thomas, Keene, Spencer, Denholm, Rachel, Akbari, Ashley, Abbasizanjani, Hoda, Torabi, Fatemeh, Omigie, Efosa, Hollings, Sam, North, Teri-Louise, Toms, Renin, Jiang, Xiyun, Angelantonio, Emanuele Di, Denaxas, Spiros, Thygesen, Johan H, Tomlinson, Christopher, Bray, Ben, Smith, Craig J, Barber, Mark, Khunti, Kamlesh, Davey Smith, George, Chaturvedi, Nishi, Sudlow, Cathie, Whiteley, William N, Wood, Angela M, Sterne, Jonathan AC, CVD-COVID-UK/COVID-IMPACT Consortium And The Longitudinal Health And Wellbeing COVID-19 National Core Study, Knight, Rochelle [0000-0002-4128-6821], Walker, Venexia [0000-0001-5064-446X], Keene, Spencer [0000-0003-0622-6476], Denholm, Rachel [0000-0002-8067-5440], Akbari, Ashley [0000-0003-0814-0801], Abbasizanjani, Hoda [0000-0002-9575-4758], Torabi, Fatemeh [0000-0002-5853-4625], Hollings, Sam [0000-0001-9022-7003], Toms, Renin [0000-0002-6922-1448], Jiang, Xiyun [0000-0003-0720-923X], Angelantonio, Emanuele Di [0000-0001-8776-6719], Thygesen, Johan H [0000-0002-7479-3459], Tomlinson, Christopher [0000-0002-0903-5395], Barber, Mark [0000-0002-2893-1566], Davey Smith, George [0000-0002-1407-8314], Chaturvedi, Nishi [0000-0002-6211-2775], Sudlow, Cathie [0000-0002-7725-7520], Whiteley, William N [0000-0002-4816-8991], Sterne, Jonathan AC [0000-0001-8496-6053], and Apollo - University of Cambridge Repository

Subjects
Adult, Venous Thrombosis, pulmonary embolism, COVID-19 Vaccines, Wales, SARS-CoV-2, COVID-19, Thrombosis, Venous Thromboembolism, stroke, Cohort Studies, electronic health records, myocardial infarction, Humans, Vascular Diseases
Abstract

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients., This work was funded by the Longitudinal Health and Wellbeing COVID-19 National Core Study, which was established by the UK Chief Scientific Officer in October 2020 and funded by UK Research and Innovation (grant references MC_PC_20030 and MC_PC_20059), by the British Heart Foundation as part of the BHF Data Science Centre led by HDR UK (BHF grant number SP/19/3/34678), and by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation(grant reference MC_PC_20058). This work uses data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make anonymised data available for research. This work was supported by the Con-COV team funded by the Medical Research Council (grant number: MR/V028367/1). This work was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-9006) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. This work was supported by core funding from the: British Heart Foundation (BHF; RG/13/13/30194; RG/18/13/33946), BHF Cambridge CRE (RE/13/6/30180) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) [*]. This work was supported by the ADR Wales programme of work. The ADR Wales programme of work is aligned to the priority themes as identified in the Welsh Government’s national strategy: Prosperity for All. ADR Wales brings together data science experts at Swansea University Medical School, staff from the Wales Institute of Social and Economic Research, Data and Methods (WISERD) at Cardiff University and specialist teams within the Welsh Government to develop new evidence which supports Prosperity for All by using the SAIL Databank at Swansea University, to link and analyse anonymised data. ADR Wales is part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1). This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales. SI was funded by a BHF-Turing Cardiovascular Data Science Award (BCDSA\100005) and is funded by a University College London FB Cancer Research UK Award (C18081/A31373). RK, JAC and JACS were supported by the NIHR Bristol Biomedical Research Centre. RK, VW GDS were supported by the MRC Integrative Epidemiology Unit at the University of Bristol. RK was supported by NIHR ARC West. RD and JACS were supported by Health Data Research UK. SK is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). TM was funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). AMW is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074 and was supported by the BHF-Turing Cardiovascular Data Science Award (BCDSA\100005). WW is supported by the Chief Scientist’s Office (CAF/01/17). CS, CS, MB AW and WW are supported by Stroke Association (SA CV 20\100018).

Published
2022

3. Parental inflammatory bowel disease and autism in children

Author

Sadik, Aws, Dardani, Christina, Pagoni, Panagiota, Havdahl, Alexandra, Stergiakouli, Evie, IPSYCH Autism Spectrum Disorder Working Group, Khandaker, Golam M, Sullivan, Sarah A, Zammit, Stan, Jones, Hannah J, Davey Smith, George, Dalman, Christina, Karlsson, Håkan, Gardner, Renee M, Rai, Dheeraj, Dardani, Christina [0000-0002-2019-7897], Havdahl, Alexandra [0000-0002-9268-0423], Stergiakouli, Evie [0000-0003-3586-0927], Davey Smith, George [0000-0002-1407-8314], Karlsson, Håkan [0000-0001-5985-7330], and Apollo - University of Cambridge Repository

Subjects
Cohort Studies, Autism Spectrum Disorder, Pregnancy, Humans, Colitis, Ulcerative, Female, General Medicine, Longitudinal Studies, Autistic Disorder, Child, Inflammatory Bowel Diseases, General Biochemistry, Genetics and Molecular Biology
Abstract

Funder: the South-Eastern Norway Regional Health Authority (2020022, 2018059) and the Research Council of Norway (274611, 288083), Funder: NIMH (1U01MH109514-01), Funder: the MQ: Transforming Mental Health (grant code: MQDS17/40), the Medical Research Council UK (grant code: MC_PC_17213 and grant code: MR/S037675/1), NIHR (project code: NIHR202646), and the BMA Foundation (J Moulton grant 2019), Funder: NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Funder: the Swedish Research Council (VR2017-02900), Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

Published
2022
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4. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, Laurence J, Nivard, Michel G, Morris, Tim T, Hansen, Ailin F, Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A, Palviainen, Teemu, Van Der Zee, Matthijs D, Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M, Bielak, Lawrence F, Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A, Reynolds, Chandra A, Balbona, Jared V, Andreassen, Ole A, Ask, Helga, Baras, Aris, Bauer, Christopher R, Boomsma, Dorret I, Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C, Dokuru, Deepika R, Evans, Luke M, De Geus, Eco JC, Giddaluru, Sudheer, Gordon, Scott D, Harden, K Paige, Hill, W David, Hughes, Amanda, Kerr, Shona M, Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A, Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik KE, Mallard, Travis T, Martikainen, Pekka, Mills, Melinda C, Njølstad, Pål Rasmus, Overton, John D, Pedersen, Nancy L, Porteous, David J, Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C, Stoltenberg, Camilla, Tucker-Drob, Elliot M, Wright, Margaret J, Social Science Genetic Association Consortium, Within Family Consortium, Hewitt, John K, Keller, Matthew C, Stallings, Michael C, Lee, James J, Christensen, Kaare, Kardia, Sharon LR, Peyser, Patricia A, Smith, Jennifer A, Wilson, James F, Hopper, John L, Hägg, Sara, Spector, Tim D, Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G, Oskarsson, Sven, Justice, Anne E, Millwood, Iona Y, Hveem, Kristian, Naess, Øyvind, Willer, Cristen J, Åsvold, Bjørn Olav, Koellinger, Philipp D, Kaprio, Jaakko, Medland, Sarah E, Walters, Robin G, Benjamin, Daniel J, Turley, Patrick, Evans, David M, Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, Davies, Neil M, Howe, Laurence J [0000-0002-2819-9686], Nivard, Michel G [0000-0003-2015-1888], Morris, Tim T [0000-0001-8178-6815], Rasheed, Humaira [0000-0002-3331-5864], Cho, Yoonsu [0000-0001-6118-6652], Lind, Penelope A [0000-0002-3887-2598], Palviainen, Teemu [0000-0002-7847-8384], van der Zee, Matthijs D [0000-0003-4076-9167], Mangino, Massimo [0000-0002-2167-7470], Wang, Yunzhang [0000-0003-1165-3595], Klaric, Lucija [0000-0003-3105-8929], Bielak, Lawrence F [0000-0002-3443-8030], Nygaard, Marianne [0000-0003-0703-2665], Giannelis, Alexandros [0000-0003-4587-0336], Willoughby, Emily A [0000-0001-7559-1544], Reynolds, Chandra A [0000-0001-6502-7173], Balbona, Jared V [0000-0003-4466-248X], Andreassen, Ole A [0000-0002-4461-3568], Ask, Helga [0000-0003-0149-5319], Baras, Aris [0000-0002-6830-3396], Boomsma, Dorret I [0000-0002-7099-7972], Campbell, Archie [0000-0003-0198-5078], Chen, Zhengming [0000-0001-6423-105X], Corfield, Elizabeth [0000-0002-0119-157X], Evans, Luke M [0000-0002-7458-1720], Gordon, Scott D [0000-0001-7623-328X], Harden, K Paige [0000-0002-1557-6737], Hughes, Amanda [0000-0001-5896-7650], Kerr, Shona M [0000-0002-4137-1495], Kweon, Hyeokmoon [0000-0002-3649-0457], Lawlor, Deborah A [0000-0002-6793-2262], Magnusson, Patrik KE [0000-0002-7315-7899], Mallard, Travis T [0000-0002-3265-3001], Martikainen, Pekka [0000-0001-9374-1438], Njølstad, Pål Rasmus [0000-0003-0304-6728], Porteous, David J [0000-0003-1249-6106], Reid, Jeffrey [0000-0001-8645-4713], Southey, Melissa C [0000-0002-6313-9005], Stoltenberg, Camilla [0000-0002-8747-1985], Tucker-Drob, Elliot M [0000-0001-5599-6237], Wright, Margaret J [0000-0001-7133-4970], Keller, Matthew C [0000-0002-6075-9882], Lee, James J [0000-0001-6547-5128], Christensen, Kaare [0000-0002-5429-5292], Peyser, Patricia A [0000-0002-9717-8459], Smith, Jennifer A [0000-0002-3575-5468], Wilson, James F [0000-0001-5751-9178], Hägg, Sara [0000-0002-2452-1500], Spector, Tim D [0000-0002-9795-0365], Plomin, Robert [0000-0002-0756-3629], Havdahl, Alexandra [0000-0002-9268-0423], Bartels, Meike [0000-0002-9667-7555], Oskarsson, Sven [0000-0001-8698-2866], Willer, Cristen J [0000-0001-5645-4966], Åsvold, Bjørn Olav [0000-0003-3837-2101], Koellinger, Philipp D [0000-0001-7413-0412], Kaprio, Jaakko [0000-0002-3716-2455], Walters, Robin G [0000-0002-9179-0321], Benjamin, Daniel J [0000-0002-2642-5416], Evans, David M [0000-0003-0663-4621], Davey Smith, George [0000-0002-1407-8314], Hayward, Caroline [0000-0002-9405-9550], Brumpton, Ben [0000-0002-3058-1059], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M [0000-0002-2460-0508], and Apollo - University of Cambridge Repository

Subjects
Multifactorial Inheritance, Phenotype, 631/208/205/2138, article, Humans, 631/208/457, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Funder: Jacobs Foundation; doi: https://doi.org/10.13039/501100003986, Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022
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5. Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease

Author

Hong Zhang, Humaira Rasheed, Yukinori Okada, Iona Y Millwood, Zhengming Chen, Tom R. Gaunt, George Davey Smith, Yoichiro Kamatani, Venexia M Walker, Philip C Haycock, Andrew P. Morris, Jie Zheng, Cristian Pattaro, Robyn E Wootton, Yuka Sugawara, Amy E Howell, Masato Akiyama, Koichi Matsuda, Sean J. Barbour, Nora Franceschini, Masahiro Kanai, Matthias Wuttke, Si Fang, Masayuki Yamamoto, Jiachen Li, Naoki Kashihara, Ben Michael Brumpton, Laurent F. Thomas, Maria Carolina Borges, Rebecca Carnegie, Jamie Robinson, Yue-miao Zhang, Stein Hallan, Canqing Yu, Benjamin Elsworth, Stephen Burgess, Yue Leng, Kristian Hveem, Robin G Walters, Yoonsu Cho, Anna Köttgen, Bjørn Olav Åsvold, Qian Yang, Zheng, Jie [0000-0002-6623-6839], Walker, Venexia [0000-0001-5064-446X], Elsworth, Benjamin [0000-0001-7328-4233], Wootton, Robyn E [0000-0003-3961-3202], Yang, Qian [0000-0001-8778-4132], Davey Smith, George [0000-0002-1407-8314], Apollo - University of Cambridge Repository, and Burgess, Stephen [0000-0001-5365-8760]

Subjects
medicine.medical_specialty, causality, Apolipoprotein B, Epidemiology, Renal function, Type 2 diabetes, urologic and male genital diseases, Random Allocation, Internal medicine, Mendelian randomization, medicine, Humans, AcademicSubjects/MED00860, Renal Insufficiency, Chronic, biology, business.industry, trans-ethnic study, General Medicine, Mendelian Randomization Analysis, medicine.disease, Causality, cardiometabolic risk factors, female genital diseases and pregnancy complications, Blood pressure, Diabetes Mellitus, Type 2, Cardiovascular Diseases, biology.protein, business, Body mass index, chronic kidney disease, Genome-Wide Association Study, Kidney disease
Abstract

Funder: Government Department of Business, Funder: Energy and Industrial Strategy (BEIS), Funder: Vice-Chancellor Fellowship from the University of Bristol, Funder: Shanghai Thousand Talents Program, Funder: Academy of Medical Sciences (AMS) Springboard Award, Funder: BBSRC Innovation fellowship, Funder: NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of 25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Published
2021

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