Search

Your search keyword '"Ong, Ken K"' showing total 174 results
Start Over Author "Ong, Ken K" Database OpenAIRE
174 results on '"Ong, Ken K"'

1. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John WR, Rainbow, Kara, Corbin, Laura J, Martin, Hilary C, Eberhardt, Ruth Y, Huang, Qin Qin, Hurles, Matthew E, He, Wen, Brauner, Raja, Delaney, Angela, Dunkel, Leo, Grinspon, Romina P, Hall, Janet E, Hirschhorn, Joel N, Howard, Sasha R, Latronico, Ana C, Jorge, Alexander AL, McElreavey, Ken, Mericq, Verónica, Merino, Paulina M, Palmert, Mark R, Plummer, Lacey, Rey, Rodolfo A, Rezende, Raíssa C, Seminara, Stephanie B, Salnikov, Kathryn, Banerjee, Indraneel, Lam, Brian YH, Perry, John RB, Timpson, Nicholas J, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, O'Rahilly, Stephen, Duckett, Katie [0000-0002-0222-1689], Williamson, Alice [0000-0002-7599-9301], Kincaid, John WR [0000-0003-0660-9813], Rainbow, Kara [0000-0002-8089-0693], Corbin, Laura J [0000-0002-4032-9500], Martin, Hilary C [0000-0002-4454-9084], Eberhardt, Ruth Y [0000-0001-6152-1369], Huang, Qin Qin [0000-0003-3073-717X], Hurles, Matthew E [0000-0002-2333-7015], Brauner, Raja [0000-0002-4456-4508], Delaney, Angela [0000-0002-0632-6365], Grinspon, Romina P [0000-0002-6291-1518], Hall, Janet E [0000-0003-4644-3061], Hirschhorn, Joel N [0000-0002-1650-7901], Palmert, Mark R [0000-0002-4096-0685], Lam, Brian YH [0000-0002-3638-9025], Timpson, Nicholas J [0000-0002-7141-9189], Clayton, Peter [0000-0003-1225-4537], Chan, Yee-Ming [0000-0003-0554-8502], Ong, Ken K [0000-0003-4689-7530], O'Rahilly, Stephen [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
UK Biobank, constitutional delay, MC3R, ALSPAC, delayed puberty
Abstract

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Published
2023
Full Text
View/download PDF

2. Leptin and IGF-1 in infancy are associated with variants in DHCR7 and CYP2R1 that relate with type 1 diabetes and 25OHD

Author

Eleftheriou, Antigoni, Ong, Ken K, Hughes, Ieuan A, Petry, Clive J, Eleftheriou, Antigoni [0000-0003-1374-719X], Ong, Ken K [0000-0003-4689-7530], Hughes, Ieuan A [0000-0002-8787-1575], Petry, Clive J [0000-0002-6642-9825], and Apollo - University of Cambridge Repository

Subjects
type 1 diabetes, IGF-1, vitamin D, early growth, leptin
Abstract

CONTEXT: Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth. OBJECTIVE: We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants. DESIGN, SETTING AND PARTICIPANTS: The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy. RESULTS: Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (β=-0.11, P=0.02) and rs12794714 (β=-0.09, P=0.04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β=0.30, P=0.01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25OHD levels, showed a positive association with leptin levels (β=0.23, P=0.009), which was pronounced in girls (P=0.004) vs. boys (P=0.7). CONCLUSIONS: The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.

Published
2023

3. 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., van Heemst, Diana, 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., Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J., Gelemanovic, Andrea, de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P., Hayward, Caroline, He, Chunyan, 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 L. R., Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, van der Most, Peter J., Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., 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, de Mutsert, Renée, Nauck, Matthias, Nolte, Ilja M., Noordam, Raymond, Penninx, Brenda W. J. H., 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 R. B., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Epidemiology, Applied Economics, Internal Medicine, Mathieson, Iain, Day, Felix R, Barban, Nicola, Tropf, Felix C, Hyppӧnen, Elina, Perry, John RB, eQTLGen Consortium, BIOS Consortium, FinnGen Study, Lifelines Cohort Study, Brazel, David M, 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, Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J, Gelemanovic, Andrea, de Geus, Eco J C, 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, Ikram, M Arfan, Jansen, Rick, Johannesson, Magnu, Kamali, Zoha, Kardia, Sharon L R, Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lind, Penelope A, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mahajan, Anubha, Martin, Nicholas G, Mbarek, Hamdi, McCarthy, Mark I, McMahon, George, Medland, Sarah E, Meitinger, Thoma, Metspalu, Andre, 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, Matthia, Nolte, Ilja M, Noordam, Raymond, Penninx, Brenda W J H, Peters, Annette, Peyser, Patricia A, Polašek, Ozren, Power, Chri, 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, Dori, 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 R B, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
Behavioral Neuroscience, Endocrine reproductive disorders Genome-wide association studies, Social Psychology, genome-wide association studies, TERM BALANCING SELECTION, QUALITY-CONTROL, ASSOCIATION, VARIANTS, GWAS, HERITABILITY, METAANALYSIS, ADAPTATION, SIGNATURES, EQTL, endocrine reproductive disorders, Experimental and Cognitive Psychology, Bristol Population Health Science Institute
Abstract

Refereed/Peer-reviewed 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

4. 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

5. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John, Rainbow, Kara, Lam, Brian, Corbin, Laura J, Martin, Hilary C., Eberhardt, Ruth Y., Huang, Qin Qin, Hurles, Matthew, Brauner, Raja, Delaney, Angela, McElreavey, Ken, Hall, Janet, Hirschhorn, Joel N, Palmert, Mark, Seminara, Stephanie, Banerjee, Indi, Perry, John R B, Timpson, Nicholas John, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, and O'Rahilly, Stephen

Subjects
ALSPAC
Abstract

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Published
2023

6. Genetic impacts on DNA methylation help elucidate regulatory genomic processes

Author

Villicaña, Sergio, Castillo-Fernandez, Juan, Hannon, Eilis, Christiansen, Colette, Tsai, Pei-Chien, Maddock, Jane, Kuh, Diana, Suderman, Matthew, Power, Christine, Relton, Caroline, Ploubidis, George, Wong, Andrew, Hardy, Rebecca, Goodman, Alissa, Ong, Ken K., and Bell, Jordana T.

Subjects
DNA methylation, meQTL, methylation quantitative trait loci, GWAS, heritability
Abstract

Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2,358 blood samples from three UK cohorts, with replication. Methylation levels at 34.2% of CpGs were affected by SNPs, and 98% of effects werecis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both meQTL SNPs and CpGs with meQTLs were overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identified 1,520 co-localisations across 1,325 unique CpGs and 34 phenotypes, including in disease-relevant genes, suchICOSLG(inflammatory bowel disease), andUSP1andDOCK7(total cholesterol levels). Enrichment analysis of meQTLs and integration with expression QTLs gave insights into mechanisms underlyingcis-meQTLs, for example through disruption of transcription factor binding sites for CTCF and SMC3, andtrans-meQTLs, for example through regulating the expression ofACDandSENP7which can modulate DNA methylation at distal sites. Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. A results database and viewer are available online.

Published
2023
Full Text
View/download PDF

7. The association between the timing, intensity and magnitude of adolescent growth and body composition in early adulthood

Author

Nyati, Lukhanyo H, Pettifor, John M, Ong, Ken K, Norris, Shane A, Nyati, Lukhanyo H [0000-0003-0975-344X], Norris, Shane A [0000-0001-7124-3788], and Apollo - University of Cambridge Repository

Subjects
Pediatric, Clinical Research, Prevention, Contraception/Reproduction, 32 Biomedical and Clinical Sciences, Obesity, Generic health relevance, 3213 Paediatrics, Metabolic and endocrine, Nutrition
Abstract

OBJECTIVES: There's paucity of longitudinal studies assessing the role of adolescent growth on adult body composition in developing countries. The aims of this study were to assess the association between adolescent change in height, weight and BMI and early adult height, weight, body fat and lean mass. METHODS: Magnitude, timing and intensity of height, weight and BMI growth were modelled for participants from the Birth to Thirty (Bt30) cohort (7-23 years). Early adult height, weight, BMI and DXA-derived body composition were obtained 1881 black participants (21-24 years). Linear regression analyses were used to assess associations. RESULTS: Adolescents with an earlier onset of puberty were heavier in childhood and had an earlier timing and faster weight gain velocity in late adolescence. The intensity of adolescent weight gain was positively associated with adult BMI and fat mass index (FMI) in females. Early timing of adolescent BMI gain was associated with increased weight and BMI in adult females and FMI in adult males. Achieving peak weight velocity around age at peak height velocity was associated with lower BMI and fat mass in both sexes. CONCLUSION: This study confirms the adverse consequences of excessive weight gain prior to puberty, which is associated with an earlier and faster resurgence in weight gain velocity in early adulthood. Factors that contribute to an asynchronous timing of ages of peak weight and peak height velocities may accentuate the risk of adult obesity.

Published
2023

8. Butyrate in Human Milk : Associations with Milk Microbiota, Milk Intake Volume, and Infant Growth

Author

Olga, Laurentya, Van Diepen, Janna A, Chichlowski, Maciej, Petry, Clive J, Vervoort, Jacques, Dunger, David B, Kortman, Guus AM, Gross, Gabriele, Ong, Ken K, Olga, Laurentya [0000-0002-3562-0598], Petry, Clive J [0000-0002-6642-9825], Kortman, Guus AM [0000-0002-8076-0661], Ong, Ken K [0000-0003-4689-7530], Apollo - University of Cambridge Repository, and Kortman, Guus A M [0000-0002-8076-0661]

Subjects
infant growth, Nutrition and Dietetics, Milk, Human, human milk microbiota, Microbiota, infant weight gain, Infant, Weight Gain, Butyrates, Breast Feeding, infant adiposity, butyrate intake, Humans, Female, Prospective Studies, Host-Microbe Interactomics, human milk intake volume, human milk butyrate, Food Science
Abstract

Peer reviewed: True, Funder: Reckitt/Mead Johnson Nutrition, Funder: National Institute for Health Research/Wellcome Trust Clinical Research Facility at Cambridge University Hospitals-NHS Foundation Trust, Funder: NIHR Cambridge Comprehensive Biomedical Research Centre, Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate's origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants (n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition (p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake.

Published
2023

9. Pre-pubertal accelerometer-assessed physical activity and timing of puberty in British boys and girls: the Millennium Cohort Study

Author

Cheng, Tuck Seng, Brage, Soren, Van Sluijs, Esther MF, Ong, Ken K, Cheng, Tuck Seng [0000-0003-4442-7332], Brage, Soren [0000-0002-1265-7355], and Apollo - University of Cambridge Repository

Subjects
Accelerometer, compositional analysis, Epidemiology, puberty timing, physical activity, substitution analysis, General Medicine
Abstract

Background Early puberty timing is associated with adverse health outcomes. We aimed to examine prospective associations between objectively measured physical activity and puberty timing in boys and girls. Methods In the UK Millennium Cohort Study, physical activity volume and intensities at 7 years were measured using accelerometers. Status of several pubertal traits and age at menarche were reported at 11, 14 and 17 years. Age at menarche in girls was categorized into tertiles. Other puberty traits were categorized into earlier or later than the median ages calculated from probit models, separately in boys and girls. Multivariable regression models, with adjustment for maternal and child characteristics including body mass index (BMI) at age 7 years as potential confounders, were performed to test the associations of total daily activity counts and fractions of activity counts across intensities (in compositional models) with puberty timing, separately in boys (n = 2531) and girls (n = 3079). Results Higher total daily activity counts were associated with lower risks for earlier (vs later) growth spurt, body hair growth, skin changes and menarche in girls, and more weakly with lower risks for earlier skin changes and voice breaking in boys (odds ratios = 0.80–0.87 per 100 000 counts/day). These associations persisted on additional adjustment for BMI at 11 years as a potential mediator. No association with puberty timing was seen for any physical activity intensity (light, moderate or vigorous). Conclusions More physical activity regardless of intensity may contribute to the avoidance of earlier puberty timing, independently of BMI, particularly in girls.

Published
2023

10. Early development of infant gut microbiota in relation to breastfeeding and human milk oligosaccharides

Author

Chichlowski, Maciej, Van Diepen, Janna A, Prodan, Andrei, Olga, Laurentya, Ong, Ken K, Kortman, Guus AM, Dunger, David B, Gross, Gabriele, and Apollo - University of Cambridge Repository

Subjects
Nutrition and Dietetics, human milk oligosaccharides (HMO), Endocrinology, Diabetes and Metabolism, microbiome, bifidobacteria, fucosyllactose, clinical, Food Science
Abstract

Peer reviewed: True, Acknowledgements: We thank study site staff for their cooperation. The participation of parents and infants in this study is greatly appreciated. We would like to thank all NIZO laboratory personnel, Dr. Sierra Durham (UC Davis) and Prof. Daniela Barile (UC Davis) for their contributions to the HMO analysis described in this manuscript. We acknowledge the CBGS research nurses Suzanne Smith, Anne-Marie Wardell, and Karen Forbes, all the families who contributed to the study, the staff at the National Institute for Health Research (NIHR) Cambridge/Wellcome Trust Clinical Research Facility, the NIHR Cambridge Comprehensive Biomedical Research Centre, the midwives at the Rosie Maternity Hospital, Cambridge, UK, and Karen Whitehead and Dianne Wingate at the Department of Paediatrics, University of Cambridge, for laboratory support., BACKGROUND: Infant gut microbiota composition is influenced by various factors early in life. Here, we investigate associations between infant gut microbiome development, infant age, breastfeeding duration, and human milk oligosaccharides (HMO) composition in breastmilk. METHODS: A total of 94 mother-infant pairs were recruited as part of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) (Cambridge, UK). Infant stool samples (n = 337) were collected at 2 week, 6 week, 3 month, and 6 month of age. The 16S rRNA V3-V4 rRNA region was sequenced using MiSeq Illumina to determine microbiota composition and diversity. Mother's hindmilk samples were collected at birth, 2 week, 6 week, 3 month, and 6 month postpartum. Concentrations of five neutral [2'FL, 3'FL, lacto-N-fucopentaose 1 (LNFP1), LNnT, LNT] and two acidic (3'SL, and 6'SL) HMOs were measured in all milk samples using High-Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD). We explored the associations between infant gut microbiome parameters and age, duration of exclusive breastfeeding (EBF), and levels of individual HMOs. RESULTS: Bifidobacterium was the most abundant genus in infant stool at all-time points, irrespective of breastfeeding duration, with an overall mean relative abundance of 70%. The relative abundance of B. bifidum in stool from infants who were breastfed for longer than 6 months was significantly higher compared to the infant breastfed up to 3 months (p = 0.0285). Alpha-diversity (both Shannon and ASV-level Richness) of infant gut microbiota showed a biphasic change with infant age, decreasing from 2 weeks until 3 months and then increasing until 6 months of age. Bifidobacterium relative abundance was associated with higher concentrations of 2'FL and LNFP1 in breastmilk across all time-points (p = 0.049 and 0.017, respectively), with trends toward a higher abundance of B. longum species. No significant association with Bifidobacterium was found for breastmilk LNnT, 3'SL, and 6'SL levels. CONCLUSION: Our study is in line with previous data demonstrating that EBF duration in the first months of life impacts infant gut microbiota composition. The observed links between specific HMOs in breastmilk and bacteria in infant stool provide evidence of how mother's milk affects infant microbiome development.

Published
2023

11. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Wielscher, Matthias, Mandaviya, Pooja R, Kuehnel, Brigitte, Joehanes, Roby, Mustafa, Rima, Robinson, Oliver, Zhang, Yan, Bodinier, Barbara, Walton, Esther, Mishra, Pashupati P, Schlosser, Pascal, Wilson, Rory, Tsai, Pei-Chien, Palaniswamy, Saranya, Marioni, Riccardo E, Fiorito, Giovanni, Cugliari, Giovanni, Karhunen, Ville, Ghanbari, Mohsen, Psaty, Bruce M, Loh, Marie, Bis, Joshua C, Lehne, Benjamin, Sotoodehnia, Nona, Deary, Ian J, Chadeau-Hyam, Marc, Brody, Jennifer A, Cardona, Alexia, Selvin, Elizabeth, Smith, Alicia K, Miller, Andrew H, Torres, Mylin A, Marouli, Eirini, Gào, Xin, Van Meurs, Joyce BJ, Graf-Schindler, Johanna, Rathmann, Wolfgang, Koenig, Wolfgang, Peters, Annette, Weninger, Wolfgang, Farlik, Matthias, Zhang, Tao, Chen, Wei, Xia, Yujing, Teumer, Alexander, Nauck, Matthias, Grabe, Hans J, Doerr, Macus, Lehtimäki, Terho, Guan, Weihua, Milani, Lili, Tanaka, Toshiko, Fisher, Krista, Waite, Lindsay L, Kasela, Silva, Vineis, Paolo, Verweij, Niek, Van Der Harst, Pim, Iacoviello, Licia, Sacerdote, Carlotta, Panico, Salvatore, Krogh, Vittorio, Tumino, Rosario, Tzala, Evangelia, Matullo, Giuseppe, Hurme, Mikko A, Raitakari, Olli T, Colicino, Elena, Baccarelli, Andrea A, Kähönen, Mika, Herzig, Karl-Heinz, Li, Shengxu, BIOS Consortium, Conneely, Karen N, Kooner, Jaspal S, Köttgen, Anna, Heijmans, Bastiaan T, Deloukas, Panos, Relton, Caroline, Ong, Ken K, Bell, Jordana T, Boerwinkle, Eric, Elliott, Paul, Brenner, Hermann, Beekman, Marian, Levy, Daniel, Waldenberger, Melanie, Chambers, John C, Dehghan, Abbas, Järvelin, Marjo-Riitta, Wielscher, Matthias [0000-0003-4138-1383], Mustafa, Rima [0000-0003-2623-5337], Robinson, Oliver [0000-0002-4735-0468], Bodinier, Barbara [0000-0002-0781-3624], Walton, Esther [0000-0002-0935-2200], Schlosser, Pascal [0000-0002-8460-0462], Wilson, Rory [0000-0001-6135-3764], Palaniswamy, Saranya [0000-0003-4145-540X], Karhunen, Ville [0000-0001-6064-1588], Ghanbari, Mohsen [0000-0002-9476-7143], Psaty, Bruce M [0000-0002-7278-2190], Loh, Marie [0000-0003-3626-8466], Bis, Joshua C [0000-0002-3409-1110], Chadeau-Hyam, Marc [0000-0001-8341-5436], Brody, Jennifer A [0000-0001-8509-148X], Cardona, Alexia [0000-0002-7877-5565], Smith, Alicia K [0000-0002-8537-5156], Miller, Andrew H [0000-0001-8260-7997], Marouli, Eirini [0000-0001-6179-1609], Gào, Xin [0000-0003-0108-6961], Koenig, Wolfgang [0000-0002-2064-9603], Peters, Annette [0000-0001-6645-0985], Farlik, Matthias [0000-0003-0698-2992], Chen, Wei [0000-0003-1566-7943], Xia, Yujing [0000-0003-0850-5591], Teumer, Alexander [0000-0002-8309-094X], Nauck, Matthias [0000-0002-6678-7964], Doerr, Macus [0000-0001-7471-475X], Lehtimäki, Terho [0000-0002-2555-4427], Milani, Lili [0000-0002-5323-3102], Fisher, Krista [0000-0002-3521-0599], van der Harst, Pim [0000-0002-2713-686X], Krogh, Vittorio [0000-0003-0122-8624], Herzig, Karl-Heinz [0000-0003-4460-2604], Li, Shengxu [0000-0001-9210-7283], Köttgen, Anna [0000-0002-4671-3714], Heijmans, Bastiaan T [0000-0001-5918-0534], Deloukas, Panos [0000-0001-9251-070X], Ong, Ken K [0000-0003-4689-7530], Bell, Jordana T [0000-0002-3858-5986], Elliott, Paul [0000-0002-7511-5684], Brenner, Hermann [0000-0002-6129-1572], Beekman, Marian [0000-0003-0585-6206], Waldenberger, Melanie [0000-0003-0583-5093], Chambers, John C [0000-0003-0209-4541], Dehghan, Abbas [0000-0001-6403-016X], Järvelin, Marjo-Riitta [0000-0002-2149-0630], Apollo - University of Cambridge Repository, Maastricht Centre for Systems Biology, RS: FSE MaCSBio, Tampere University, Clinical Medicine, Department of Clinical Chemistry, BioMediTech, Department of Clinical Physiology and Nuclear Medicine, Ong, Kenneth [0000-0003-4689-7530], Internal Medicine, and Epidemiology

Subjects
obesity, BLOOD, 45/61, PREDICTION, NF-KAPPA-B, BIOS consortium, General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, 38, Low grade inflammation, MARKERS, SDG 3 - Good Health and Well-being, Inflammation/genetics, risk factors, Medicine, Humans, TRANSCRIPTION, Nucleotide Motifs, C-Reactive Protein, CpG Islands, DNA Methylation, Inflammation, EPIGENOME-WIDE ASSOCIATION, DNA methylation, Multidisciplinary, business.industry, article, 631/208/176/1988, 692/163/2743/393, Cardiorespiratory fitness, General Chemistry, CpG Islands/genetics, LIFETIME RISK, GENOME, BODY-MASS INDEX, Immunology, 3111 Biomedicine, C-Reactive Protein/genetics, business, 692/499, DNA Methylation/genetics
Abstract

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Published
2022

12. 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, Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexis, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johannes, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Markus, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthias, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Markus, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashis, Scholz, Markus, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., 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., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Hyppӧnen, Elina, Ikram, M. Arfan, Johannesson, Magnus, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chris, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Doris, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Snieder, Harold, Perry, John R. B., Ong, Ken K., den Hoed, Marcel, Barban, Nicola, Day, Felix R., Mills, M. C., Tropf, F. C., Brazel, D. M., van Zuydam, N., Vaez, A., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A. K., Arindrarto, W., Awadalla, P., Battle, A., Beutner, F., Jan Bonder, M., Boomsma, D. I., Christiansen, M. W., Claringbould, A., Deelen, P., Esko, T., Fave, M. -J., Franke, L., Frayling, T., Gharib, S. A., Gibson, G., Heijmans, B. T., Hemani, G., Jansen, R., Kahonen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg, J., Kukushkina, V., Kutalik, Z., Lee, B., Lehtimaki, T., Loeffler, M., Marigorta, U. M., Mei, H., Milani, L., Montgomery, G. W., Muller-Nurasyid, M., Nauck, M., Nivard, M. G., Penninx, B. W. J. H., Perola, M., Pervjakova, N., Pierce, B. L., Powell, J., Prokisch, H., Psaty, B. M., Raitakari, O. T., Ripatti, S., Rotzschke, O., Rueger, S., Saha, A., Scholz, M., Schramm, K., Seppala, I., Slagboom, E. P., Stehouwer, C. D. A., Stumvoll, M., Sullivan, P., 't Hoen, P. A. C., Teumer, A., Thiery, J., Tong, L., Tonjes, A., van Dongen, J., van Iterson, M., van Meurs, J., Veldink, J. H., Verlouw, J., Visscher, P. M., Volker, U., Vosa, U., Westra, H. -J., Wijmenga, C., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., van Greevenbroek, M. M. J., Schalkwijk, C. G., Deelen, J., van Heemst, D., van Duijn, C. M., Hofman, B. A., Isaacs, A., Uitterlinden, A. G., Verbiest, M., Suchiman, H. E. D., Verkerk, M., van der Breggen, R., van Rooij, J., Lakenberg, N., Bot, J., Zhernakova, D. V., Luijk, R., Bonder, M. J., Swertz, M. A., van Zwet, E. W., Akimova, E. T., Bergmann, S., Boardman, J. D., Buring, J. E., Cesarini, D., Chasman, D. I., Chavarro, J. E., Cocca, M., Concas, M. P., Davey-Smith, G., Davies, G., Deary, I. J., Gaskins, A. J., de Geus, E. J. C., Gieger, C., Girotto, G., Grabe, H. J., Gunderson, E. P., Harris, K. M., Hartwig, F. P., He, C., Homuth, G., Horta, B. L., Jan Hottenga, J., Huang, H., Hyppӧnen, E., Ikram, M. A., Johannesson, M., Kamali, Z., Kavousi, M., Kraft, P., Kuhnel, B., Langenberg, C., Study, L. C., Lind, P. A., Luan, J., Magi, R., Magnusson, P. K. E., Mahajan, A., Martin, N. G., Mbarek, H., Mccarthy, M. I., Mcmahon, G., Mcqueen, M. B., Medland, S. E., Meitinger, T., Metspalu, A., Mihailov, E., Missmer, S. A., Mollegaard, S., Mook-Kanamori, D. O., Morgan, A., van der Most, P. J., de Mutsert, R., Noordam, R., Power, C., Redmond, P., Rich-Edwards, J. W., Ridker, P. M., Rietveld, C. A., Ring, S. M., Rose, L. M., Rueedi, R., Stefansson, K., Stockl, D., Strauch, K., Thurik, A. R., Timpson, N. J., Turman, C., Wareham, N. J., Willemsen, G., Zhao, J. H., Pers, T. H., Snieder, H., Perry, J. R. B., Ong, K. K., den Hoed, M., Barban, N., Day, F. R., Mills, Melinda C, Tropf, Felix C, Brazel, David M, van Zuydam, Natalie, Vaez, Ahmad, Pers, Tune H, Snieder, Harold, Perry, John RB, Ong, Ken K, den Hoed, Marcel, Barban, Nicola, Day, Felix R, Hyppӧnen, Elina, eQTLGen Consortium, BIOS Consortium, Human Reproductive Behaviour Consortium, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Consortium, eQTLGen, Consortium, BIOS, Consortium, Human Reproductive Behaviour, Mahajan, A, McCarthy, MI, Mills, Melinda C., Tropf, Felix C., Brazel, David M., Agbessi, Mawussé, Ahsan, Habibul, Alves, Isabel, Andiappan, Anand Kumar, Arindrarto, Wibowo, Awadalla, Philip, Battle, Alexi, Beutner, Frank, Jan Bonder, Marc, Boomsma, Dorret I., Christiansen, Mark W., Claringbould, Annique, Deelen, Patrick, Esko, Tõnu, Favé, Marie-Julie, Franke, Lude, Frayling, Timothy, Gharib, Sina A., Gibson, Greg, Heijmans, Bastiaan T., Hemani, Gibran, Jansen, Rick, Kähönen, Mika, Kalnapenkis, Anette, Kasela, Silva, Kettunen, Johanne, Kim, Yungil, Kirsten, Holger, Kovacs, Peter, Krohn, Knut, Kronberg, Jaanika, Kukushkina, Viktorija, Kutalik, Zoltan, Lee, Bernett, Lehtimäki, Terho, Loeffler, Marku, Marigorta, Urko M., Mei, Hailang, Milani, Lili, Montgomery, Grant W., Müller-Nurasyid, Martina, Nauck, Matthia, Nivard, Michel G., Penninx, Brenda W. J. H., Perola, Marku, Pervjakova, Natalia, Pierce, Brandon L., Powell, Joseph, Prokisch, Holger, Psaty, Bruce M., Raitakari, Olli T., Ripatti, Samuli, Rotzschke, Olaf, Rüeger, Sina, Saha, Ashi, Scholz, Marku, Schramm, Katharina, Seppälä, Ilkka, Slagboom, Eline P., Stehouwer, Coen D. A., Stumvoll, Michael, Sullivan, Patrick, ‘t Hoen, Peter A. C., Teumer, Alexander, Thiery, Joachim, Tong, Lin, Tönjes, Anke, van Dongen, Jenny, van Iterson, Maarten, van Meurs, Joyce, Veldink, Jan H., Verlouw, Joost, Visscher, Peter M., Völker, Uwe, Võsa, Urmo, Westra, Harm-Jan, Wijmenga, Cisca, Yaghootkar, Hanieh, Yang, Jian, Zeng, Biao, Zhang, Futao, Isaacs, Aaron, Pool, René, Jan Hottenga, Jouke, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Sasha, Tigchelaar, Ettje F., Beekman, Marian, Deelen, Jori, van Heemst, Diana, van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Nooren, Irene, Moed, Matthij, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., Akimova, Evelina T., Bergmann, Sven, Boardman, Jason D., 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., Franco, Oscar, Gaskins, Audrey J., de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Grabe, Hans Jörgen, Gunderson, Erica P., Harris, Kathleen Mullan, Hartwig, Fernando P., He, Chunyan, Hill, W. David, Homuth, Georg, Horta, Bernando Lessa, Huang, Hongyang, Ikram, M. Arfan, Johannesson, Magnu, Kamali, Zoha, Kavousi, Maryam, Kraft, Peter, Kühnel, Brigitte, Langenberg, Claudia, Lind, Penelope A., Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, McQueen, Matthew B., Medland, Sarah E., Meitinger, Thoma, Metspalu, Andre, Mihailov, Evelin, Missmer, Stacey A., Møllegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter J., de Mutsert, Renée, Nolte, Ilja M., Noordam, Raymond, Peters, Annette, Power, Chri, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Stefánsson, Kári, Stöckl, Dori, Strauch, Konstantin, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Waldenberger, Melanie, Wareham, Nicholas J., Willemsen, Gonneke, Zhao, Jing Hau, Pers, Tune H., Perry, John R. B., Ong, Ken K., Day, Felix R., Sociology [until 2010], Biological Psychology, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Management and Organisation, Urology, Medical Informatics, Department of Marketing Management, Epidemiology, Internal Medicine, Radiology & Nuclear Medicine, Neurology, Applied Economics, and Life Course Epidemiology (LCE)

Subjects
Male, demography, genetic variants, reproductive biology, externalising behavior, environmental effects, Disease, Genome-wide association studies, Behavioral Neuroscience, 0302 clinical medicine, genetics, media_common, fertility, 0303 health sciences, Reproduction, Incidence (epidemiology), Coitus, Age Factors, Longevity, sexual intercourse, health, Spermatid differentiation, Single Nucleotide, Reproduction/genetics, 3. Good health, Behavioural genetics, Parturition/genetics, Female, infertility, Infertility, genetic variant, Adolescent, Social Psychology, media_common.quotation_subject, Experimental and Cognitive Psychology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Reproductive biology, medicine, Humans, Polymorphism, behavioural genetics, first sexual intercourse, Genetic Association Studies, Demography, 030304 developmental biology, Parturition, Coitus/physiology, medicine.disease, externalising behaviour, Sexual intercourse, Fertility, age, 030217 neurology & neurosurgery, first birth
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

13. 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

14. Early childhood weight gain: Latent patterns and body composition outcomes

Author

Norris, Tom, Mansukoski, Liina, Gilthorpe, Mark S., Hamer, Mark, Hardy, Rebecca, Howe, Laura D., Li, Leah, Ong, Ken K., Ploubidis, George B., Viner, Russell M., Johnson, William, Norris, Tom [0000-0002-9140-0776], Ong, Ken K [0000-0003-4689-7530], Apollo - University of Cambridge Repository, and Ong, Ken K. [0000-0003-4689-7530]

Subjects
body composition, growth, Body Weight, weight, ALSPAC, Weight Gain, Body Mass Index, Pregnancy, Child, Preschool, Humans, Female, Longitudinal Studies, Obesity, ORIGINAL ARTICLES, Child, ORIGINAL ARTICLE, childhood
Abstract

Background: Despite early childhood weight gain being a key indicator of obesity risk, we do not have a good understanding of the different patterns that exist. Objectives: To identify and characterise distinct groups of children displaying similar early‐life weight trajectories. Methods: A growth mixture model captured heterogeneity in weight trajectories between 0 and 60 months in 1390 children in the Avon Longitudinal Study of Parents and Children. Differences between the classes in characteristics and body size/composition at 9 years were investigated. Results: The best model had five classes. The “Normal” (45%) and “Normal after initial catch‐down” (24%) classes were close to the 50th centile of a growth standard between 24 and 60 months. The “High‐decreasing” (21%) and “Stable‐high” (7%) classes peaked at the ~91st centile at 12‐18 months, but while the former declined to the ~75th centile and comprised constitutionally big children, the latter did not. The “Rapidly increasing” (3%) class gained weight from below the 50th centile at 4 months to above the 91st centile at 60 months. By 9 years, their mean body mass index (BMI) placed them at the 98th centile. This class was characterised by the highest maternal BMI; highest parity; highest levels of gestational hypertension and diabetes; and the lowest socio‐economic position. At 9 years, the “Rapidly increasing” class was estimated to have 68.2% (95% confidence interval [CI] 48.3, 88.1) more fat mass than the “Normal” class, but only 14.0% (95% CI 9.1, 18.9) more lean mass. Conclusions: Criteria used in growth monitoring practice are unlikely to consistently distinguish between the different patterns of weight gain reported here.

Published
2021
Full Text
View/download PDF

15. Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study

Author

Petry, Clive J, Hughes, Ieuan A, Ong, Ken K, Petry, Clive J [0000-0002-6642-9825], and Apollo - University of Cambridge Repository

Subjects
Male, Insulin secretion, Fetal sex, Development, Cohort Studies, Gender Studies, Glucose, Fetus, Endocrinology, Pregnancy, Humans, Insulin, Female, Insulin Resistance, Gestational diabetes
Abstract

Background It has been suggested that fetal sex may be able to modify maternal metabolism and physiology during pregnancy. Recently pregnant women carrying a male fetus were reported to be more insulin sensitive than those carrying females, although related evidence is inconsistent. Methods In this study we administered a 75 g oral glucose tolerance test at around week 28 of pregnancy in 813 pregnant women from a contemporary birth cohort (the Cambridge Baby Growth Study), derived surrogate indices of insulin secretion and sensitivity, and related them to the fetal sex. Results Carrying a male fetus was associated with lower fasting glucose (difference in mean concentrations ≈ 0.1 mmol/L; β′ = 0.063; p = 0.02) and insulin (≈ 1.1 pmol/L; β′ = 0.075; p = 0.01) concentrations but not with post-load glucose or insulin concentrations. Male fetal sex was also associated with lower HOMA IR (≈ 1.08 units; β′ = 0.071; p = 0.02) and higher QUICKI (≈ 1.06 units; β′ = 0.080; p = 0.007) values suggesting increased basal insulin sensitivity. There were no differences in indices of insulin secretion, except for the insulin disposition index which was higher in women carrying a male fetus (≈ 1.15 units; β′ = 0.090; p = 0.007). Birth weights were higher in male offspring. Conclusions Women carrying a male fetus were relatively more insulin sensitive in the fasting state and secreted more insulin relative to this degree of insulin sensitivity. These results are consistent with the idea that the fetal sex may be able to modify the maternal glucose-insulin axis.

Published
2022

16. Lipid profiling analyses from mouse models and human infants

Author

Olga, Laurentya, Bobeldijk-Pastorova, Ivana, Bas, Richard C, Seidel, Florine, Snowden, Stuart G, Furse, Samuel, Ong, Ken K, Kleemann, Robert, Koulman, Albert, Ong, Kenneth [0000-0003-4689-7530], Koulman, Albert [0000-0001-9998-051X], and Apollo - University of Cambridge Repository

Subjects
General Immunology and Microbiology, Mass spectrometry, General Neuroscience, Health sciences, Infant, FOS: Health sciences, Lipids, General Biochemistry, Genetics and Molecular Biology, Mice, Disease Models, Animal, Metabolism, Lipidomics, Metabolomics, Humans, Animals, Clinical protocol, Systems biology
Abstract

This protocol outlines a translational lipidomic approach to discover lipid biomarkers that could predict morphometric body and histological organ measurements (e.g., weight and adiposity gains) during specific stages of life (e.g., early life). We describe procedures ranging from animal experimentation and histological analyses to downstream analytical steps through lipid profiling, both in mice and humans. This protocol represents a reliable and versatile approach to translate and validate candidate lipid biomarkers from animal models to a human cohort. For complete details on the use and execution of this protocol, please refer to Olga et al. (2021).

Published
2022

20. Associations between Children's Genetic Susceptibility to Obesity, Infant's Appetite and Parental Feeding Practices in Toddlerhood

Author

Guivarch, Claire, Charles, Marie-Aline, Forhan, Anne, Ong, Ken K, Heude, Barbara, De Lauzon-Guillain, Blandine, Guivarch, Claire [0000-0002-5415-6954], Charles, Marie-Aline [0000-0003-4025-4390], Ong, Ken K [0000-0003-4689-7530], Heude, Barbara [0000-0002-1565-1629], de Lauzon-Guillain, Blandine [0000-0001-5887-8842], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Parents, Pediatric Obesity, Appetite, Infant, birth cohort, eating behavior, genetic susceptibility to obesity, Humans, Female, Genetic Predisposition to Disease, Infant Food, Longitudinal Studies, parental feeding practices
Abstract

Previous findings suggest that parental feeding practices may adapt to children's eating behavior and sex, but few studies assessed these associations in toddlerhood. We aimed to study the associations between infant's appetite or children's genetic susceptibility to obesity and parental feeding practices. We assessed infant's appetite (three-category indicator: low, normal or high appetite, labelled 4-to-24-month appetite) and calculated a combined obesity risk-allele score (genetic risk score of body mass index (BMI-GRS)) in a longitudinal study of respectively 1358 and 932 children from the EDEN cohort. Parental feeding practices were assessed at 2-year-follow-up by the CFPQ. Three of the five tested scores were used as continuous variables; others were considered as binary variables, according to the median. Associations between infant's appetite or child's BMI-GRS and parental feeding practices were assessed by linear and logistic regression models, stratified on child's sex if interactions were significant. 4-to-24-month appetite was positively associated with restrictive feeding practices among boys and girls. Among boys, high compared to normal 4-to-24-month appetite was associated with higher use of food to regulate child's emotions (OR [95% CI] = 2.24 [1.36; 3.68]). Child's BMI-GRS was not related to parental feeding practices. Parental feeding practices may adapt to parental perception of infant's appetite and child's sex.

Published
2021
Full Text
View/download PDF

21. Genetic analyses identify widespread sex-differential participation bias

Author

Pirastu, Nicola, Cordioli, Mattia, Nandakumar, Priyanka, Mignogna, Gianmarco, Abdellaoui, Abdel, Hollis, Benjamin, Kanai, Masahiro, Rajagopal, Veera M, Parolo, Pietro Della Briotta, Baya, Nikolas, Carey, Caitlin E, Karjalainen, Juha, Als, Thomas D, Van Der Zee, Matthijs D, Day, Felix R, Ong, Ken K, FinnGen Study, 23andMe Research Team, IPSYCH Consortium, Morisaki, Takayuki, De Geus, Eco, Bellocco, Rino, Okada, Yukinori, Børglum, Anders D, Joshi, Peter, Auton, Adam, Hinds, David, Neale, Benjamin M, Walters, Raymond K, Nivard, Michel G, Perry, John RB, Ganna, Andrea, Pirastu, Nicola [0000-0002-5363-3886], Cordioli, Mattia [0000-0002-4872-0520], Mignogna, Gianmarco [0000-0002-3989-7180], Abdellaoui, Abdel [0000-0003-1088-6784], Kanai, Masahiro [0000-0001-5165-4408], Rajagopal, Veera M [0000-0002-5236-168X], Baya, Nikolas [0000-0002-4681-374X], Als, Thomas D [0000-0002-2963-1928], Van der Zee, Matthijs D [0000-0003-4076-9167], Day, Felix R [0000-0003-3789-7651], Ong, Ken K [0000-0003-4689-7530], Okada, Yukinori [0000-0002-0311-8472], Børglum, Anders D [0000-0001-8627-7219], Joshi, Peter [0000-0002-6361-5059], Hinds, David [0000-0002-4911-803X], Neale, Benjamin M [0000-0003-1513-6077], Walters, Raymond K [0000-0001-8422-6530], Perry, John RB [0000-0001-6483-3771], Ganna, Andrea [0000-0002-8147-240X], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Sex Characteristics, Inheritance Patterns, Polymorphism, Single Nucleotide, United Kingdom, Bias, Genetic Loci, Sample Size, Chromosomes, Human, Humans, Female, Artifacts, Biological Specimen Banks, Genome-Wide Association Study
Abstract

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Published
2021

22. Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan

Author

Hollis, Ben, Day, Felix R., Busch, Alexander S., Thompson, Deborah J., Soares, Ana Luiza G., Timmers, Paul R. H. J., Kwong, Alex, Easton, Doug F., Joshi, Peter K., Timpson, Nicholas J., Ong, Ken K., Perry, John R. B., Eeles, Rosalind A., Henderson, Brian E., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Muir, Kenneth, Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Gapstur, Susan, Stevens, Victoria L., Tangen, Catherine M., Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Cancel-Tassin, Géraldine, Koutros, Stella, Sorensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Gago-Dominguez, Manuela, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Tilley, Wayne, Risbridger, Gail P., Horvath, Lisa, Taylor, Renea, Hayes, Vanessa, Butler, Lisa, Yeadon, Trina, Eckert, Allison, Saunders, Pamela, Haynes, Anne-Maree, Papargiris, Melissa, Srinivasan, Srilakshmi, Kedda, Mary-Anne, Moya, Leire, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Day, Felix R. [0000-0003-3789-7651], Busch, Alexander S. [0000-0003-4417-569X], Thompson, Deborah J. [0000-0003-1465-5799], Soares, Ana Luiza G. [0000-0003-2763-4647], Timmers, Paul R. H. J. [0000-0002-5197-1267], Kwong, Alex [0000-0003-1953-2771], Easton, Doug F. [0000-0003-2444-3247], Joshi, Peter K. [0000-0002-6361-5059], Timpson, Nicholas J. [0000-0002-7141-9189], Ong, Ken K. [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
631/443/494, 631/208/205/2138, 692/308/2056, 45/43, article, 692/163
Abstract

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.

Published
2020

23. The association between age at menarche and later risk of gestational diabetes is mediated by insulin resistance

Author

Petry, Clive J., Ong, Ken K., Hughes, Ieuan A., Acerini, Carlo L., Dunger, David B., Petry, Clive J [0000-0002-6642-9825], Ong, Ken K [0000-0003-4689-7530], Hughes, Ieuan A [0000-0002-8787-1575], Acerini, Carlo L [0000-0003-2121-5871], Dunger, David B [0000-0002-2566-9304], and Apollo - University of Cambridge Repository

Subjects
Adult, Blood Glucose, Male, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Physiology, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Pregnancy, Risk Factors, Insulin-Secreting Cells, Diabetes mellitus, Internal Medicine, medicine, Humans, Insulin, Prospective Studies, 030212 general & internal medicine, Child, Prospective cohort study, Adiposity, Menarche, business.industry, Puberty, Age Factors, Infant, Newborn, Insulin sensitivity, General Medicine, medicine.disease, 3. Good health, Gestational diabetes, Diabetes, Gestational, Original Article, Female, PAPP-A, Insulin Resistance, business
Abstract

Aims Associations have been reported between age at menarche and the later risk of gestational diabetes. However, it is not known whether these associations reflect differences in insulin sensitivity and/or pancreatic β-cell function in pregnancy. Methods We examined this question in women enrolled in the prospective Cambridge Baby Growth Study who recalled their age at menarche in questionnaires during pregnancy. Polynomial logistic and linear regression models were used to relate menarche timing to the risk of gestational diabetes, both unadjusted and adjusted for the Homeostasis Model Assessments of insulin resistance (HOMA IR) and pancreatic β-cell function (HOMA B) at week 28 of pregnancy. Results Age at menarche showed a U-shaped association with gestational diabetes risk (linear term: p = 9.5 × 10−4; quadratic term: p = 1.0 × 10−3; n = 889; overall model p = 8.1 × 10−3). Age at menarche showed a negative linear association with insulin resistance (HOMA IR: β = −0.13, p = 5.2 × 10−4, n = 771), which explained the relationship between age at menarche and gestational diabetes risk (adjusted linear term going from p = 0.03–0.08; adjusted quadratic term going from p = 0.04–0.08; n = 771). Age at menarche also showed a negative linear association with β-cell function (HOMA B: β = −0.11, p = 2.8 × 10−3, n = 771) but this did not attenuate the relationship between age at menarche and gestational diabetes (adjusted linear term p = 0.02; adjusted quadratic term p = 0.03, n = 771). Conclusions These results suggest that the associations between age at menarche and risk of gestational diabetes and raised pregnancy glucose concentrations may be mediated by insulin resistance. Electronic supplementary material The online version of this article (10.1007/s00592-018-1162-7) contains supplementary material, which is available to authorized users.

Published
2018

26. A polygenic risk score to predict future adult short stature amongst children

Author

Lu, Tianyuan, Forgetta, Vincenzo, Wu, Haoyu, Perry, John R.B., Ong, Ken K., Greenwood, Celia, Timpson, Nicholas, Manousaki, Despoina, and Richards, Brent

Abstract

Supplementary Notes, Tables and Figures for journal article. Full article published in The Journal of Clinical Endocrinology & Metabolism https://doi.org/10.1210/clinem/dgab215. The polygenic risk score is available on the PGS Catalog https://www.pgscatalog.org/score/PGS000758/.Important note (Aug 2021): SNPs included in this polygenic risk score may be imputed. For imputed SNPs, probability-based dosages (continuous values ranging from 0 to 2) should be used to calculate the score rather than hard-coded dosages (0/1/2). Extra caution must be taken if using programs by default rounding dosages to integers such as plink(2). Important note (Mar 2022): We spotted a mistake in the previously submitted version of the score file, as some of the predictor SNPs had effect / alternative alleles mistakenly flipped. We have included a corrected version in this repository and are contacting the PGS Catalog to correct deposited file as well. TL sincerely apologizes for this mistake.

Published
2021
Full Text
View/download PDF

27. Relative effects of postnatal rapid growth and maternal factors on early childhood growth trajectories

Author

Zheng, Miaobing, Bowe, Steven J, Hesketh, Kylie D, Bolton, Kristy, Laws, Rachel, Kremer, Peter, Ong, Ken K, Lioret, Sandrine, Denney-Wilson, Elizabeth, Campbell, Karen J, Zheng, Miaobing [0000-0002-4151-3502], Ong, Ken K [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
Male, Pediatric Obesity, growth, Australia, Infant, Newborn, Infant, Nutritional Status, determinants, Nutrition Surveys, Body Height, Body Mass Index, maternal, trajectory, Child, Preschool, InFANT program, Humans, Female, Longitudinal Studies, Waist Circumference, Child Nutritional Physiological Phenomena, Infant Nutritional Physiological Phenomena
Abstract

BACKGROUND: A range of postnatal and maternal factors influences childhood obesity, but their relative importance remains unclear. This study aimed to assess the relative impact of postnatal rapid growth and maternal factors on early childhood growth trajectories. SUBJECTS: Secondary longitudinal analysis of pooled data from the Melbourne Infant Feeding Activity and Nutrition Trial (InFANT) Program and the InFANT Extend Program (n = 977) was performed. Children's height and weight were collected at birth, 3, 9, 18, and 36/42 months. Body mass index-for-age and height-for-age z-scores (BAZ, HAZ) were computed using WHO growth standards. Mixed-effect polynomial regression models were fitted to examine BAZ and HAZ trajectories and their determinants. RESULTS: Rapid growth from birth to 3 months, maternal country of birth, and pre-pregnancy BMI were each independently associated with BAZ from 3 to 42 months. Children with rapid growth, those whose mothers were Australian-born, and those whose mothers were overweight/obese pre-pregnancy had higher BAZ from 3 to 42 months. Children with rapid growth had an increase in HAZ growth, but their average HAZ from 3 to 42 months was smaller than children without rapid growth. Children of tall mothers (above average height) had higher HAZ than those of short mothers (below average height). Average HAZ from 3 to 42 months did not differ by maternal country of birth. CONCLUSION: Children who experienced rapid growth from birth to 3 months, whose mothers were Australian-born or whose mothers were overweight/obese pre-pregnancy demonstrated less favourable growth trajectories across early childhood, potentially predispose them for development of future obesity.

Published
2019
Full Text
View/download PDF

28. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan J M, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A J, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M T, Uitterlinden, Andre G, Schierding, William, O'Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra I F, Ong, Ken K, Jaddoe, Vincent W V, Grant, Struan F A, Sebert, Sylvain, McCarthy, Mark I, Järvelin, Marjo-Riitta, Erasmus MC other, Epidemiology, Internal Medicine, Pediatrics, Medical Research Council (MRC), Sovio, Ulla [0000-0002-0799-1105], Perry, John [0000-0001-6483-3771], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Warrington, Nicole M [0000-0003-4195-775X], Lewin, Alexandra M [0000-0003-0081-7582], Kaakinen, Marika [0000-0002-9228-0462], Cousminer, Diana L [0000-0001-8864-7893], Timpson, Nicholas J [0000-0002-7141-9189], Lowry, Estelle [0000-0002-4655-416X], Brown, Christopher D [0000-0002-3785-5008], Estivill, Xavier [0000-0002-0723-2256], Geller, Frank [0000-0002-9238-3269], Speed, Doug [0000-0002-0096-9765], Coin, Lachlan J M [0000-0002-4300-455X], Loh, Marie [0000-0003-3626-8466], Barton, Sheila J [0000-0003-4963-4242], Alili, Rohia [0000-0002-0158-4250], Schramm, Katharina [0000-0002-8809-3170], Charles, Marie-Aline [0000-0003-4025-4390], Claringbould, Annique A J [0000-0002-9201-6557], van Duijn, Cornelia M [0000-0002-2374-9204], Feenstra, Bjarke [0000-0003-1478-649X], Frayling, Timothy M [0000-0001-8362-2603], Freathy, Rachel M [0000-0003-4152-2238], Widén, Elisabeth [0000-0001-7108-2806], Hakonarson, Hakon [0000-0003-2814-7461], Rodriguez, Alina [0000-0003-1209-8802], Heude, Barbara [0000-0002-1565-1629], Holloway, John W [0000-0001-9998-0464], Hofman, Albert [0000-0002-9865-121X], Hyppönen, Elina [0000-0003-3670-9399], Inskip, Hazel [0000-0001-8897-1749], Kaplan, Lee M [0000-0002-6301-2696], Prokisch, Holger [0000-0003-2379-6286], Lakka, Timo A [0000-0002-9199-2871], Lawlor, Debbie A [0000-0002-6793-2262], Melbye, Mads [0000-0001-8264-6785], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Marinelli, Marcella [0000-0002-5450-3960], Palmer, Lyle J [0000-0002-1628-3055], Pennell, Craig E [0000-0002-0937-6165], Perry, John R [0000-0001-6483-3771], Ring, Susan M [0000-0003-3103-9330], Savolainen, Markku J [0000-0002-2557-6423], Rivadeneira, Fernando [0000-0001-9435-9441], Sunyer, Jordi [0000-0002-2602-4110], Schierding, William [0000-0001-5659-2701], O'Sullivan, Justin M [0000-0003-2927-450X], Prokopenko, Inga [0000-0003-1624-7457], Smith, George Davey [0000-0002-1407-8314], Felix, Janine F [0000-0002-9801-5774], Ong, Ken K [0000-0003-4689-7530], Jaddoe, Vincent W V [0000-0003-2939-0041], Sebert, Sylvain [0000-0001-6681-6983], McCarthy, Mark I [0000-0002-4393-0510], and Järvelin, Marjo-Riitta [0000-0002-2149-0630]

Subjects
Adult, Male, Pharmacogenomic Variants, Quantitative Trait Loci, BLOOD-PRESSURE, 030209 endocrinology & metabolism, Polymorphism, Single Nucleotide, Body Mass Index, EARLY-LIFE, 03 medical and health sciences, AGE, Quantitative Trait, Heritable, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Longitudinal Studies, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, METABOLIC RISK, Growth Charts, FTO GENE, Child, Research Articles, Genetic Association Studies, Adaptor Proteins, Signal Transducing, 2. Zero hunger, Science & Technology, BIRTH COHORT, Intracellular Signaling Peptides and Proteins, nutritional and metabolic diseases, SciAdv r-articles, Infant, Human Genetics, Genomics, 3. Good health, Multidisciplinary Sciences, BODY-MASS INDEX, OBESITY, Science & Technology - Other Topics, Receptors, Leptin, ADIPOSITY, Female, biological, Research Article, Genome-Wide Association Study
Abstract

Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

29. GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis

Author

Chadda, Karan R, Cheng, Tuck Seng, Ong, Ken K, Chadda, Karan R [0000-0002-8060-8408], Cheng, Tuck Seng [0000-0003-4442-7332], and Apollo - University of Cambridge Repository

Subjects
obesity, Pediatric Obesity, pediatric, glucagon-like peptide-1, Adolescent, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1, Humans, Hypoglycemic Agents, type 2 diabetes, Child, Glucagon-Like Peptide-1 Receptor, Randomized Controlled Trials as Topic
Abstract

Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged

Published
2020
Full Text
View/download PDF

30. Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity

Author

Mills, Melinda C., Tropf, Felix C., Brazel, David M., van Zuydam, Natalie, Vaez, Ahmad, Pers, Tune H., Snieder, Harold, Perry, John R.B., Ong, Ken K., Hoed, Marcel den, Barban, Nicola, and Day, Felix R.

Abstract

The timing of reproductive behaviour – age at first sexual intercourse (AFS) and age at first birth (AFB) – has implications for reproductive health, adolescent development and evolutionary fitness. In the largest genome-wide association study to date (AFS, N=387,338; AFB, N=542,901), we identify 370 independent signals, 11 which are sex-specific, with a 5-6% polygenic score prediction. Heritability shifted from 10% for those born in 1940 to 23% for the 1965 birth cohort. Using Genomic SEM, we show that signals are largely driven by the genetics of reproductive biology and externalizing behaviour. This is supported by extensive biological follow-up that isolates key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility (endometriosis, spontaneous abortion) and spermatid differentiation, morphogenesis and binding (KLF17, ZPBP). Later AFB is protective against later-life disease (type 2 diabetes, cardiovascular) and associated with longevity. Those from higher childhood socioeconomic circumstances and polygenic scores in the highest deciles (90%+) experience markedly later reproductive onset. Results are relevant for interventions in teenage sexual, reproductive and mental health, deepen our understanding of the drivers of later-life health and longevity, and fuel infertility and functional follow-up experiments.

Published
2020
Full Text
View/download PDF

31. Genetic analyses identify widespread sex-differential participation bias

Author

Pirastu, Nicola, Cordioli, Mattia, Nandakumar, Priyanka, Mignogna, Gianmarco, Abdellaoui, Abdel, Hollis, Benjamin, Kanai, Masahiro, Rajagopal, Veera M., Della Briotta Parolo, Pietro, Baya, Nikolas, Carey, Caitlin, Karjalainen, Juha, Als, Thomas D., Van der Zee, Matthijs D., Day, Felix R., Ong, Ken K., Study, Finngen, Morisaki, Takayuki, de Geus, Eco, Bellocco, Rino, Okada, Yukinori, Børglum, Anders D., Joshi, Peter, Auton, Adam, Hinds, David, Neale, Benjamin M., Walters, Raymond K., Nivard, Michel G., Perry, John R.B., Ganna, Andrea, and Adult Psychiatry

Subjects
0303 health sciences, Participation bias, Locus (genetics), Genome-wide association study, Heritability, Biology, 03 medical and health sciences, 0302 clinical medicine, Sample size determination, Allele, 10. No inequality, Body mass index, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association, Demography
Abstract

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of this participation bias is challenging as it requires the genotypes of unseen individuals. However, we demonstrate that it is possible to estimate comparative biases by performing GWAS contrasting one subgroup versus another. For example, we show that sex exhibits autosomal heritability in the presence of sex-differential participation bias. By performing a GWAS of sex in ~3.3 million males and females, we identify over 158 autosomal loci significantly associated with sex and highlight complex traits underpinning differences in study participation between sexes. For example, the body mass index (BMI) increasing allele at the FTO locus was observed at higher frequency in males compared to females (OR 1.02 [1.02-1.03], P=4.4×10−36). Finally, we demonstrate how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Published
2020

32. Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19delta13

Author

Petry, Clive J, Evans, Mark L, Wingate, Dianne L, Ong, Ken K, Reik, Wolf, Constância, Miguel, Dunger, David B, Petry, Clive [0000-0002-6642-9825], Evans, Mark [0000-0001-8122-8987], Ong, Kenneth [0000-0003-4689-7530], Reik, Wolf [0000-0003-0216-9881], Dunger, David [0000-0002-2566-9304], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, Male, Genome, RNA, Untranslated, Genetic Variation, Glucose Tolerance Test, Pedigree, Pregnancy Complications, Diabetes, Gestational, Genomic Imprinting, Mice, Fetus, Insulin-Like Growth Factor II, Pregnancy, Hyperglycemia, embryonic structures, Animals, Insulin, Female, RNA, Long Noncoding
Abstract

OBJECTIVE: We have hypothesized that variation in imprinted growth-promoting fetal genes may affect maternal glucose concentrations in pregnancy. To test this hypothesis we evaluated the effects of fetal disruption of murine H19(Delta13) on maternal glucose concentrations in pregnancy. RESEARCH DESIGN AND METHODS: Experimental mice were pregnant females that had inherited the disrupted H19(Delta13) from their fathers and were therefore phenotypically wild type due to imprinting; approximately half of their litters were null for H19(Delta13) through maternal inheritance of the disrupted gene. In control mice approximately half the litter paternally inherited the disrupted H19(Delta13), so the pups were either genetically wild type or phenotypically wild type due to imprinting. Blood glucose concentrations were assessed by intraperitoneal glucose tolerance tests on days 1, 16, and 18 of pregnancy. RESULTS: There were no differences in the glucose concentrations of control and experimental pregnant mice at day 1. However, at day 16 mothers carrying H19(Delta13)-null pups had a significantly higher area under the glucose tolerance test curves than controls (1,845 +/- 378 vs. 1,386 +/- 107 mmol * min * l(-1) [P = 0.01]) in association with increasing pregnancy-related insulin resistance. Although this difference lessened toward term, overall, mothers of maternally inherited H19(Delta13) mutants had significantly higher glucose concentrations during the last trimester (1,602 +/- 321 [n = 17] vs. 1,359 +/- 147 [n = 18] mmol * min * l(-1) [P = 0.009]). CONCLUSIONS: This study provides evidence that maternal glucose concentrations in pregnant mice can be affected by targeted disruption of fetal H19(Delta13). This implies that variable fetal IGF2 expression could affect risk for gestational diabetes.

Published
2020
Full Text
View/download PDF

33. Using human genetics to understand the disease impacts of testosterone in men and women

Author

Ruth, Katherine S, Day, Felix R, Tyrrell, Jessica, Thompson, Deborah J, Wood, Andrew R, Mahajan, Anubha, Beaumont, Robin N, Wittemans, Laura, Martin, Susan, Busch, Alexander S, Erzurumluoglu, A Mesut, Hollis, Benjamin, O'Mara, Tracy A, Endometrial Cancer Association Consortium, McCarthy, Mark I, Langenberg, Claudia, Easton, Douglas F, Wareham, Nicholas J, Burgess, Stephen, Murray, Anna, Ong, Ken K, Frayling, Timothy M, Perry, John RB, Day, Felix R [0000-0003-3789-7651], Martin, Susan [0000-0001-8746-0947], Busch, Alexander S [0000-0003-4417-569X], Erzurumluoglu, A Mesut [0000-0003-1322-8138], O'Mara, Tracy A [0000-0002-5436-3232], Langenberg, Claudia [0000-0002-5017-7344], Easton, Douglas F [0000-0003-2444-3247], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Male, Estradiol, Genotype, Prostatic Neoplasms, Breast Neoplasms, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, United Kingdom, Endometrial Neoplasms, Phenotype, Sex Factors, Diabetes Mellitus, Type 2, Haplotypes, Body Composition, Odds Ratio, Cluster Analysis, Humans, Female, Testosterone, Biomarkers, Software, Biological Specimen Banks, Genome-Wide Association Study, Polycystic Ovary Syndrome
Abstract

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

Published
2019
Full Text
View/download PDF

34. Associations between the maternal circulating lipid profile in pregnancy and fetal imprinted gene alleles: a cohort study

Author

Petry, Clive J, Koulman, Albert, Lu, Liangjian, Jenkins, Benjamin, Furse, Samuel, Prentice, Philippa, Matthews, Lee, Hughes, Ieuan A, Acerini, Carlo L, Ong, Ken K, Dunger, David B, Apollo - University of Cambridge Repository, and Petry, Clive J [0000-0002-6642-9825]

Subjects
Adult, Genotype, Parent-of-origin, lcsh:QH471-489, Development, Lipids, Polymorphism, Single Nucleotide, lcsh:Gynecology and obstetrics, Mass Spectrometry, Cohort Studies, Diabetes, Gestational, Genomic Imprinting, Fetus, Gene Frequency, Haplotypes, Pregnancy, Lipidomics, Humans, lcsh:Reproduction, Female, Lipid profiling, Alleles, Triglycerides, Gestational diabetes, lcsh:RG1-991
Abstract

Background Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. Methods Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n = 200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n = 567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. Results The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R = 0.14, p = 2.9 × 10− 3, n = 386) and maternally-transmitted fetal FAM99A rs7131362 (R = 0.18, p = 6.2 × 10− 3, n = 351; association with maternal-untransmitted allele R = 0.08, p = 0.07, n = 328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10− 3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). Conclusions Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.

Published
2018

35. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Author

Lee, James J., Wedow, Robbee, Okbay, Aysu, Kong, Edward, Maghzian, Omeed, Zacher, Meghan, Nguyen-Viet, Tuan Anh, Bowers, Peter, Sidorenko, Julia, Karlsson Linnér, Richard, Fontana, Mark Alan, Kundu, Tushar, Lee, Chanwook, Hui, Li, Ruoxi, Li, Royer, Rebecca, Timshel, Pascal N., Walters, Raymond K., Willoughby, Emily A., Yengo, Loïc, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Hinds, David A., Mccreight, Jennifer C., Huber, Karen E., Litterman, Nadia K., Mcintyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Vacic, Vladimir, Wilson, Catherine H., Beauchamp, Jonathan P., Pers, Tune H., Rietveld, Cornelius A., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Meddens, S. Fleur W., Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, Vlaming, Ronald de, Abdellaoui, Abdel, Ahluwalia, Tarunveer S., Bacelis, Jonas, Baumbach, Clemens, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Furlotte, Nicholas A., Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, van der Lee, Sven J., Leeuw, Christiaan de, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., van der Most, Peter J., Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J., Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm-Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klaus, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Panos, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Joshi, Peter K., Jugessur, Astanand, Kaakinen, Marika A., Kähönen, Mika, Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Kutalik, Zoltan, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, LifeLines Cohort Study, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Meddens, Gerardus A., Mcmahon, George, Meisinger, Christa, Meitinger, Thomas, Milaneschi, Yusplitri, Milani, Lili, Montgomery, Grant W., Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, van Rooij, Frank J. A., Venturini, Cristina, Vinkhuyzen, Anna A. E., Völker, Uwe, Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johannes, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klaus, Bertram, Lars, Bisgaard, Hans, Boomsma, Dorret I., Borecki, Ingrid B., Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., van Duijn, Cornelia M., Eriksson, Johan G., Franke, Barbara, Franke, Lude, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, van der Harst, Pim, Hayward, Caroline, Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehtimäki, Terho, Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Metspalu, Andres, Pendleton, Neil, Penninx, Brenda W. J. H., Perola, Markus, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Tung, Joyce Y., Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Yang, Jian, Johannesson, Magnus, Visscher, Peter M., Esko, Tõnu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., Alver, Maris, Bao, Yanchun, Clark, David W., Day, Felix R., Kemper, Kathryn E., Kleinman, Aaron, Langenberg, Claudia, Trampush, Joey W., Verma, Shefali Setia, Yang, Wu, Lam, Max, Zhao, Jing Hua, Zheng, Zhili, Boardman, Jason D., Freese, Jeremy, Harris, Kathleen Mullan, Herd, Pamela, Kumari, Meena, Lencz, Todd, Luan, Jian’An, Malhotra, Anil K., Ong, Ken K., Perry, John R. B., Ritchie, Marylyn D., Smart, Melissa C., Wareham, Nicholas J., Robinson, Matthew R., Watson, Chelsea, Lee, James J, Wedow, Robbee, Okbay, Aysu, Kong, Edward, Hyppönen, Elina, Cesarini, David, 23andMe Research Team, COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, LifeLines Cohort Study, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Lee, James J., Maghzian, Omeed, Zacher, Meghan, Nguyen-Viet, Tuan Anh, Bowers, Peter, Sidorenko, Julia, Karlsson Linnér, Richard, Fontana, Mark Alan, Kundu, Tushar, Lee, Chanwook, Li, Hui, Li, Ruoxi, Royer, Rebecca, Timshel, Pascal N., Walters, Raymond K., Willoughby, Emily A., Yengo, Loïc, Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Hinds, David A., Mccreight, Jennifer C., Huber, Karen E., Litterman, Nadia K., Mcintyre, Matthew H., Mountain, Joanna L., Noblin, Elizabeth S., Northover, Carrie A. M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Vacic, Vladimir, Wilson, Catherine H., Beauchamp, Jonathan P., Pers, Tune H., Rietveld, Cornelius A., Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Meddens, S. Fleur W., Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, Vlaming, Ronald de, Abdellaoui, Abdel, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, Maria Pina, Derringer, Jaime, Furlotte, Nicholas A., Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, van der Lee, Sven J., Leeuw, Christiaan de, Lind, Penelope A., Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., van der Most, Peter J., Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J., Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm-Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Heath, Andrew C., Hocking, Lynne J., Holliday, Elizabeth G., Homuth, Georg, Horan, Michael A., Hottenga, Jouke-Jan, de Jager, Philip L., Joshi, Peter K., Jugessur, Astanand, Kaakinen, Marika A., Kähönen, Mika, Kanoni, Stavroula, Keltigangas-Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Kutalik, Zoltan, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, LifeLines Cohort, Study, Anu, Madden, Pamela A., Mägi, Reedik, Mäki-Opas, Tomi, Marioni, Riccardo E., Marques-Vidal, Pedro, Meddens, Gerardus A., Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Milani, Lili, Montgomery, Grant W., Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Räikkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti-Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen-Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, van Rooij, Frank J. A., Venturini, Cristina, Vinkhuyzen, Anna A. E., Völker, Uwe, Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Boomsma, Dorret I., Borecki, Ingrid B., Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., van Duijn, Cornelia M., Eriksson, Johan G., Franke, Barbara, Franke, Lude, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans-Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, van der Harst, Pim, Hayward, Caroline, Hoffmann, Wolfgang, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo-Riitta, Jöckel, Karl-Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehtimäki, Terho, Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Metspalu, Andre, Pendleton, Neil, Penninx, Brenda W. J. H., Perola, Marku, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Tung, Joyce Y., Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Smith, George Davey, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Yang, Jian, Johannesson, Magnu, Visscher, Peter M., Esko, Tõnu, Koellinger, Philipp D., Benjamin, Daniel J., Alver, Mari, Bao, Yanchun, Clark, David W., Day, Felix R., Kemper, Kathryn E., Kleinman, Aaron, Langenberg, Claudia, Trampush, Joey W., Verma, Shefali Setia, Wu, Yang, Lam, Max, Zhao, Jing Hua, Zheng, Zhili, Boardman, Jason D., Freese, Jeremy, Harris, Kathleen Mullan, Herd, Pamela, Kumari, Meena, Lencz, Todd, Luan, Jian’An, Malhotra, Anil K., Ong, Ken K., Perry, John R. B., Ritchie, Marylyn D., Smart, Melissa C., Wareham, Nicholas J., Robinson, Matthew R., Watson, Chelsea, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Department of Health and Life Sciences, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Neurology, Psychiatry, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Medical Oncology, Applied Economics, Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Cappuccio, Francesco

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, genetic association, LOCI, Medizin, Genome-wide association study, INTELLIGENCE, Cohort Studies, 0302 clinical medicine, GWAS, Genetics, Aged, 80 and over, Genome, HERITABILITY, HUMAN TRAITS, Middle Aged, HUMAN BRAIN, STATISTICS, 3. Good health, Phenotype, Meta-analysis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], educational attainment, POPULATIONS, Educational Status, Female, genome-wide-significant SNPs, SDG 4 - Quality Education, Adult, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SNP, Humans, QH426, Behavioural genetics, METAANALYSIS, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Sequence Analysis, DNA, Heritability, Educational attainment, polygenic prediction, 030104 developmental biology, Genome-Wide Association Study, MAPPING CAUSAL VARIANTS, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 195595.pdf (Publisher’s version ) (Open Access) Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Published
2018

36. Systematic review indicates postnatal growth in term infants born small-for-gestational-age being associated with later neurocognitive and metabolic outcomes

Author

Castanys-Muñoz, Esther, Kennedy, Kathy, Castañeda-Gutiérrez, Eurídice, Forsyth, Stewart, Godfrey, Keith M., Koletzko, Berthold, Ozanne, Susan E., Rueda, Ricardo, Schoemaker, Marieke H., van der Beek, Eline M., van Buuren, Stef, Ong, Ken K., Methodology and statistics for the behavioural and social sciences, and Leerstoel van Buuren

Subjects
Pediatrics, Neurodevelopment, Blood Pressure, BLOOD-PRESSURE, Review Article, Weight Gain, 0302 clinical medicine, Child Development, Cognition, Medicine, Review Articles, Adiposity, Postnatal growth, INSULIN SENSITIVITY, General Medicine, Small for gestational age, Perinatology, Lipids, WEIGHT-GAIN, and Child Health, Infant, Small for Gestational Age, medicine.symptom, medicine.medical_specialty, CATCH-UP GROWTH, Birth weight, 030209 endocrinology & metabolism, ADIPONECTIN LEVELS, 03 medical and health sciences, Insulin resistance, 030225 pediatrics, PRETERM INFANTS, Humans, Pediatrics, Perinatology, and Child Health, business.industry, Infant, Newborn, medicine.disease, LIPID PROFILE, BIRTH-WEIGHT, BODY-MASS INDEX, Blood pressure, PROSPECTIVE COHORT, Pediatrics, Perinatology and Child Health, Lean body mass, business, Body mass index, Neurocognitive, Weight gain
Abstract

We systematically reviewed papers published in English between 1994 and October 2015 on how postnatal weight gain and growth affect neurodevelopment and metabolic outcomes in term‐born small‐for‐gestational‐age (SGA) infants. Two randomised trials reported that enriched infant formulas that promoted early growth also increased fat mass, lean mass and blood pressure (BP), but had no effect on early neurocognitive outcomes. Meanwhile, 31 observational studies reported consistent positive associations between postnatal weight gain and growth with neurocognitive outcomes, adiposity, insulin resistance and BP. Conclusion: Few intervention studies exist, despite consistent positive associations between early growth and neurocognition in term‐born SGA infants.

Published
2017

37. Using genetics to disentangle the complex relationship between food choices and health status

Author

Pirastu, Nicola, McDonnell, Ciara, Grzeszkowiak, Eryk J., Mounier, Ninon, Imamura, Fumiaki, Day, Felix R., Zheng, Jie, Taba, Nele, Concas, Maria Pina, Repetto, Linda, Kentistou, Katherine A., Robino, Antonietta, Esko, Tõnu, Joshi, Peter K., Fischer, Krista, Ong, Ken K., Gaunt, Tom R., Kutalik, Zoltan, Perry, John R. B., and Wilson, James F.

Abstract

Despite food choices being one of the most important factors influencing health, efforts to identify individual food groups and dietary patterns that cause disease have been challenging, with traditional nutritional epidemiological approaches plagued by biases and confounding. After identifying 302 (289 novel) individual genetic determinants of dietary intake in 445,779 individuals in the UK Biobank study, we develop a statistical genetics framework that enables us, for the first time, to directly assess the impact of food choices on health outcomes. We show that the biases which affect observational studies extend also to GWAS, genetic correlations and causal inference through genetics, which can be corrected by applying our methods. Finally, by applying Mendelian Randomization approaches to the corrected results we identify some of the first robust causal associations between eating patterns and risks of cancer, heart disease and obesity, distinguishing between the effects of specific foods or dietary patterns.

Published
2019
Full Text
View/download PDF

38. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Da Silva Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bonnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clement, Karine, Claringbould, Annique A.J, Consortium, BIOS, van Duijin, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliot, Paul, Widen, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hypponen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Laara, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M.T, Uitterlinden, Andre G., Schierding, William, O'Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra L. F, Ong, Ken K., Jaddoe, Vincent W.V, Grant, Struan F.A, Sebert, Sylvain, McCarthy, Mark L., and Jarvelin, Marjo-Riitta

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

39. 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
Full Text
View/download PDF

40. Effects of dietary intake patterns from 1 to 4 years on BMI z-score and body shape at age of 6 years: a prospective birth cohort study from Brazil

Author

Santos, Leonardo Pozza, Ong, Ken K, Santos, Ina S, Matijasevich, Alicia, Barros, Aluísio JD, Santos, Leonardo Pozza [0000-0002-3993-3786], and Apollo - University of Cambridge Repository

Subjects
Male, Infant, Feeding Behavior, Diet, Body Mass Index, Cohort Studies, Body shape, Breast Feeding, Food intake, Child, Preschool, Body Composition, Humans, Female, Longitudinal Studies, Prospective Studies, Snacks, Child, Brazil
Abstract

PURPOSE: To assess the association between dietary intake patterns from 1 to 4 years and BMI and body shape at age of 6 years. METHODS: This longitudinal study was based on 3374 Brazilian children from the 2004 Pelotas Birth Cohort Study. We used previously described dietary patterns from 1 to 4 years as the main exposure. We defined body shape using scores for corpulence (a recently described body shape component measured by Photonic Scanner), and trunk and gynoid fat mass percentage from DXA. We run linear regression models to evaluate the associations between dietary patterns from 1 to 4 years and BMI and body shape at 6 years. RESULTS: Several apparent associations between dietary patterns and BMI or body shape were explained by sociodemographic factors. High adherence to snacks (positive loadings to coffee, bread and cookies) at 4 years predicted lower BMI, but higher gynoid fat mass percentage at 6 years, while higher adherence to staple at 2 years (positive loadings to rice and beans) predicted higher trunk fat mass and lower gynoid fat mass. Finally, higher scores on milks at 1 year (positive loading to breast milk) predicted higher gynoid fat mass at 6 years. CONCLUSION: There were inconsistent associations between dietary patterns in infancy and early childhood and BMI and body shape at 6 years. In adjusted analyses, higher adherence to breast milk at 1 year and to snacks at 4 years appeared to be beneficial for body shape, associated with lower BMI, but higher peripheral fat.

Published
2019

41. Systematic review and meta-analysis of the association between childhood physical activity and age at menarche

Author

Calthorpe, Lucia, Brage, Soren, Ong, Ken K, Calthorpe, Lucia [0000-0002-0496-9471], and Apollo - University of Cambridge Repository

Subjects
Age at menarche, Menarche, Athlete, Physical activity, Age Factors, Humans, Puberty timing, Exercise
Abstract

AIM: To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM). METHODS: We searched PubMed (1990-2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population-based studies and a random-effects meta-analysis of results of athlete/nonathlete studies. RESULTS: One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two-year study period (relative risk: 0.75, 95% CI: 0.66-0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self-reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta-analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80-1.47) in athletes compared to nonathletes. CONCLUSION: These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population-based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours.

Published
2019

42. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer Singh, Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., and Felix, Janine F.

Subjects
ddc:570, Institut für Biochemie und Biologie
Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

Published
2019

43. Association between genetic obesity susceptibility and mother-reported eating behaviour in children up to 5 years

Author

De Lauzon-Guillain, Blandine, Koudou, Yves Akoli, Botton, Jérémie, Forhan, Anne, Carles, Sophie, Pelloux, Véronique, Clément, Karine, Ong, Ken K, Charles, Marie Aline, Heude, Barbara, and EDEN Mother-Child Cohort Study Group

Subjects
eating behaviour, growth, birth cohort, genetic
Abstract

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI., The EDEN study is supported by Fondation pour la Recherche Médicale (FRM), French Ministry of Research: Federative Research Institutes and Cohort Program, INSERM Human Nutrition National Research Program, and Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients [AFD]), French Ministry of Health, French Agency for Environment Security (AFSSET), French National Institute for Population Health Surveillance (InVS), Paris‐Sud University, French National Institute for Health Education (INPES), Nestlé, Mutuelle Générale de l'Education Nationale (MGEN), French‐speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM), National Agency for Research (ANR non‐thematic programme), and National Institute for Research in Public Health (IRESP: TGIR 2008 cohort in health programme). The genotyping was funded by a Collaborative Research Grant from the European Society for Paediatric Endocrinology. K.K.O. is supported by the Medical Research Council (unit program: MC_UU_12015/2).

Published
2019
Full Text
View/download PDF

44. Systematic review and meta-analysis of the association between childhood physical activity and age at menarche

Author

Calthorpe, Lucia, Brage, Soren, and Ong, Ken K

Subjects
Age at menarche, Menarche, Athlete, Physical activity, Age Factors, Humans, Puberty timing, Exercise
Abstract

AIM: To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM). METHODS: We searched PubMed (1990-2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population-based studies and a random-effects meta-analysis of results of athlete/nonathlete studies. RESULTS: One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two-year study period (relative risk: 0.75, 95% CI: 0.66-0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self-reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta-analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80-1.47) in athletes compared to nonathletes. CONCLUSION: These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population-based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours.

Published
2019
Full Text
View/download PDF

45. Association between genetic obesity susceptibility and mother-reported eating behaviour in children up to 5 years

Author

de Lauzon-Guillain, Blandine, Koudou, Yves Akoli, Botton, Jérémie, Forhan, Anne, Carles, Sophie, Pelloux, Véronique, Clément, Karine, Ong, Ken K, Charles, Marie Aline, Heude, Barbara, EDEN Mother-Child Cohort Study Group, Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
eating behaviour, growth, birth cohort, genetic
Abstract

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI.

Published
2019

46. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Author

Kraja, Aldi T, Liu, Chunyu, Fetterman, Jessica L, Graff, Mariaelisa, Have, Christian Theil, Gu, Charles, Yanek, Lisa R, Feitosa, Mary F, Arking, Dan E, Chasman, Daniel I, Young, Kristin, Ligthart, Symen, Hill, W David, Weiss, Stefan, Luan, Jian'an, Giulianini, Franco, Li-Gao, Ruifang, Hartwig, Fernando P, Lin, Shiow J, Wang, Lihua, Richardson, Tom G, Yao, Jie, Fernandez, Eliana P, Ghanbari, Mohsen, Wojczynski, Mary K, Lee, Wen-Jane, Argos, Maria, Armasu, Sebastian M, Barve, Ruteja A, Ryan, Kathleen A, An, Ping, Baranski, Thomas J, Bielinski, Suzette J, Bowden, Donald W, Broeckel, Ulrich, Christensen, Kaare, Chu, Audrey Y, Corley, Janie, Cox, Simon R, Uitterlinden, Andre G, Rivadeneira, Fernando, Cropp, Cheryl D, Daw, E Warwick, Van Heemst, Diana, De Las Fuentes, Lisa, Gao, He, Tzoulaki, Ioanna, Ahluwalia, Tarunveer S, De Mutsert, Renée, Emery, Leslie S, Erzurumluoglu, A Mesut, Perry, James A, Fu, Mao, Forouhi, Nita G, Gu, Zhenglong, Hai, Yang, Harris, Sarah E, Hemani, Gibran, Hunt, Steven C, Irvin, Marguerite R, Jonsson, Anna E, Justice, Anne E, Kerrison, Nicola D, Larson, Nicholas B, Lin, Keng-Hung, Love-Gregory, Latisha D, Mathias, Rasika A, Lee, Joseph H, Nauck, Matthias, Noordam, Raymond, Ong, Ken K, Pankow, James, Patki, Amit, Pattie, Alison, Petersmann, Astrid, Qi, Qibin, Ribel-Madsen, Rasmus, Rohde, Rebecca, Sandow, Kevin, Schnurr, Theresia M, Sofer, Tamar, Starr, John M, Taylor, Adele M, Teumer, Alexander, Timpson, Nicholas J, De Haan, Hugoline G, Wang, Yujie, Weeke, Peter E, Williams, Christine, Wu, Hongsheng, Yang, Wei, Zeng, Donglin, Witte, Daniel R, Weir, Bruce S, Wareham, Nicholas J, Vestergaard, Henrik, Turner, Stephen T, Torp-Pedersen, Christian, Stergiakouli, Evie, Sheu, Wayne Huey-Herng, Rosendaal, Frits R, Ikram, M Arfan, Franco, Oscar H, Ridker, Paul M, Perls, Thomas T, Pedersen, Oluf, Nohr, Ellen A, Newman, Anne B, Linneberg, Allan, Langenberg, Claudia, Kilpeläinen, Tuomas O, Kardia, Sharon LR, Jørgensen, Marit E, Jørgensen, Torben, Sørensen, Thorkild IA, Homuth, Georg, Hansen, Torben, Goodarzi, Mark O, Deary, Ian J, Christensen, Cramer, Chen, Yii-Der Ida, Chakravarti, Aravinda, Brandslund, Ivan, Bonnelykke, Klaus, Taylor, Kent D, Wilson, James G, Rodriguez, Santiago, Davies, Gail, Horta, Bernardo L, Thyagarajan, Bharat, Rao, DC, Grarup, Niels, Davila-Roman, Victor G, Hudson, Gavin, Guo, Xiuqing, Arnett, Donna K, Hayward, Caroline, Vaidya, Dhananjay, Mook-Kanamori, Dennis O, Tiwari, Hemant K, Levy, Daniel, Loos, Ruth JF, Dehghan, Abbas, Elliott, Paul, Malik, Afshan N, Scott, Robert A, Becker, Diane M, De Andrade, Mariza, Province, Michael A, Meigs, James B, Rotter, Jerome I, North, Kari E, Epidemiology, Internal Medicine, Gastroenterology & Hepatology, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Luan, Jian'an [0000-0003-3137-6337], Erzurumluoglu, Mesut [0000-0003-1322-8138], Forouhi, Nita [0000-0002-5041-248X], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
insulin, HbA1c, MT-nDNA candidate genes, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 610 Medicine & health, ATHEROSCLEROSIS RISK, waist-to-hip ratio, PERIPHERAL-BLOOD, DNA, Mitochondrial, Article, HOMA-IR, Body Mass Index, Cohort Studies, BMI, 360 Social problems & social services, Adipocytes, Diabetes Mellitus, GLYCEMIC TRAITS, Humans, INDIVIDUALS REVEAL, GENOME-WIDE ASSOCIATION, glucose, Glycated Hemoglobin, Genetics & Heredity, Science & Technology, Waist-Hip Ratio, mtDNA, Genetic Variation, COMMON VARIANTS, HOMA-B, 11 Medical And Health Sciences, DNA COPY NUMBER, 06 Biological Sciences, BODY-MASS INDEX, mitochondria, Genes, Mitochondrial, Metabolism, ADIPOSE-TISSUE, Cardiovascular Diseases, Life Sciences & Biomedicine
Abstract

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

Published
2019

47. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Pediatrics, Epidemiology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Public and occupational health, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, Epidemiology and Data Science, Medical Research Council (MRC), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Faculty of Medicine, Timo Strandberg / Principal Investigator, Department of Medicine, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Developmental Psychology Research Group, Genetic Epidemiology, Genomic Discoveries and Clinical Translation, Cognitive and Brain Aging, Middeldorp, Christel M [0000-0002-6218-0428], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), embarazo, Epidemiology, C840 Clinical Psychology, LD SCORE REGRESSION, humanos, LOCI, Medizin, adolescente, Genome-wide association study, BLOOD-PRESSURE, Disease, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Pregnancy, Medicine, 030212 general & internal medicine, Early childhood, C820 Developmental Psychology, estudios de cohortes, Child, C440 Molecular Genetics, Public, Environmental & Occupational Health, Genetics, education.field_of_study, United Kingdom/epidemiology, COMMON VARIANTS, Hälsovetenskaper, adulto, A900 Others in Medicine and Dentistry, 3142 Public health care science, environmental and occupational health, 3. Good health, predicción, ddc, Childhood traits and disorders, Phenotype, Disease/genetics, Research Design, Child, Preschool, fenotipo, Female, ICEP, medicine.symptom, CHILDHOOD OBESITY, Life Sciences & Biomedicine, EArly Genetics Lifecourse Epidemiology (EAGLE) consortium, Adult, medicine.medical_specialty, Adolescent, Birth weight, Population, Consortium, Childhood Traits And Disorders, Longitudinal, enfermedad, Childhood obesity, 1117 Public Health and Health Services, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Health Sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, LONGITUDINAL TWIN, METAANALYSIS, lactante, Science & Technology, Early Growth Genetics (EGG) consortium, business.industry, Infant, Newborn, Infant, predisposición genética a la enfermedad, medicine.disease, BODY-MASS, C800 Psychology, BIRTH-WEIGHT, C420 Human Genetics, United Kingdom, Low birth weight, business, diseño de la investigación, Forecasting
Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Published
2019

48. Breast milk nutrient content and infancy growth

Author

Prentice, Philippa, Ong, Ken K., Schoemaker, Marieke H., van Tol, Eric A.F., Vervoort, Jacques, Hughes, Ieuan A., Acerini, Carlo L., Dunger, David B., Ong, Kenneth [0000-0003-4689-7530], Acerini, Carlo [0000-0003-2121-5871], Dunger, David [0000-0002-2566-9304], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Breast milk, Milk, Human, Breastfeeding, Infant, Newborn, Biochemie, Infant, Regular Article, Growth, Weight, Biochemistry, Lipids, Child Development, Humans, Female, Macronutrients, Prospective Studies, VLAG, Regular Articles, Nutrition
Abstract

Aim Benefits of human breast milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient content. We tested the hypothesis that differential HM total calorie content (TCC) or macronutrient contents may be associated with infancy growth. Methods HM hindmilk samples were collected at ages 4–8 weeks from 614 mothers participating in a representative birth cohort, with repeated infancy anthropometry. HM triglyceride (fat), lipid analytes and lactose (carbohydrate) were measured by 1H‐NMR, and protein content by the Dumas method. TCC and %macronutrients were determined. Results In 614 HM samples, fat content was as follows: [median(IQR)]: 2.6 (1.7–3.6) g/100 mL, carbohydrate: 8.6 (8.2–8.8) g/100 mL, protein: 1.2 (1.1–1.2) g/100 mL; TCC: 61.8 (53.7–71.3) kcal/100 mL. HM of mothers exclusively breast feeding vs. mixed feeding was more calorific with higher %fat, lower %carbohydrate and lower %protein. Higher HM TCC was associated with lower 12‐months body mass index (BMI)/adiposity, and lower 3–12 months gains in weight/BMI. HM %fat was inversely related to 3–12 months gains in weight, BMI and adiposity, whereas %carbohydrate was positively related to these measures. HM %protein was positively related to 12‐months BMI. Conclusion HM analysis showed wide variation in %macronutrients. Although data on milk intakes were unavailable, our findings suggest functional relevance of HM milk composition to infant growth.

Published
2016

49. Socioeconomic conditions across life related to multiple measures of the endocrine system in older adults: Longitudinal findings from a British birth cohort study

Author

Bann, David, Hardy, Rebecca, Cooper, Rachel, Lashen, Hany, Keevil, Brian, Wu, Frederick C.W., Holly, Jeff M.P., Ong, Ken K., Ben-Shlomo, Yoav, and Kuh, Diana

Subjects
Thyroid, Male, Endocrine System, Socioeconomic factors, Middle Aged, Cortisol, United Kingdom, Health(social science), Cohort Studies, Insulin-like growth factors, Social Class, Journal Article, Humans, Testosterone, Female, Longitudinal Studies, Healthcare Disparities
Abstract

BACKGROUND: Little is known about how socioeconomic position (SEP) across life impacts on different axes of the endocrine system which are thought to underlie the ageing process and its adverse consequences. We examined how indicators of SEP across life related to multiple markers of the endocrine system in late midlife, and hypothesized that lower SEP across life would be associated with an adverse hormone profile across multiple axes.METHODS: Data were from a British cohort study of 875 men and 905 women followed since their birth in March 1946 with circulating free testosterone and insulin-like growth factor-I (IGF-I) measured at both 53 and 60-64 years, and evening cortisol at 60-64 years. Indicators of SEP were ascertained prospectively across life-paternal occupational class at 4, highest educational attainment at 26, household occupational class at 53, and household income at 60-64 years. Associations between SEP and hormones were investigated using multiple regression and logistic regression models.RESULTS: Lower SEP was associated with lower free testosterone among men, higher free testosterone among women, and lower IGF-I and higher evening cortisol in both sexes. For example, the mean standardised difference in IGF-I comparing the lowest with the highest educational attainment at 26 years (slope index of inequality) was -0.4 in men (95% CI -0.7 to -0.2) and -0.4 in women (-0.6 to -0.2). Associations with each hormone differed by SEP indicator used and sex, and were particularly pronounced when using a composite adverse hormone score. For example, the odds of having 1 additional adverse hormone concentration in the lowest compared with highest education level were 3.7 (95% CI: 2.1, 6.3) among men, and 1.6 (1.0, 2.7) among women (P (sex interaction) = 0.02). We found no evidence that SEP was related to apparent age-related declines in free testosterone or IGF-I.CONCLUSIONS: Lower SEP was associated with an adverse hormone profile across multiple endocrine axes. SEP differences in endocrine function may partly underlie inequalities in health and function in later life, and may reflect variations in biological rates of ageing. Further studies are required to assess the likely functional relevance of these associations.

Published
2015
Full Text
View/download PDF

50. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A. J., van Duijn, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M. T., Uitterlinden, Andre G., Schierding, William, O’Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra I. F., Ong, Ken K., Jaddoe, Vincent W. V., Grant, Struan F. A., Sebert, Sylvain, McCarthy, Mark I., and Järvelin, Marjo-Riitta

Subjects
ddc
Published
2018

Catalog

Books, media, physical & digital resources
See catalog results