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1.  The association of birth order with later body mass index and blood pressure: a comparison between prospective cohort studies from the UK and Brazil 
Background
Previous studies have found greater adiposity and cardiovascular risk in first born children. The causality of this association is not clear. Examining the association in diverse populations may lead to improved insight.
Methods
We examine the association between birth order and body mass index (BMI), systolic and diastolic blood pressure (SBP/DBP) in the 2004 Pelotas cohort from southern Brazil and the Avon Longitudinal Study of Parents and Children (ALSPAC) from Bristol, south west England, restricting analysis to families with two children in order to remove confounding by family size.
Results
No consistent differences in BMI, SBP or DBP were observed comparing first and second born children. Within the Pelotas 2004 cohort, first born females were thinner, with lower SBP and DBP; e.g. mean difference in SBP comparing first with second born was -0.979 (95% confidence interval -2.901 to 0.943). In ALSPAC, first born females had higher BMI, SBP and DBP. In both cohorts, associations tended to be in the opposite direction in males, although no statistical evidence for gender interactions was found.
Conclusions
The findings do not support an association between birth order and BMI or blood pressure. Differences to previous studies may be explained by differences in populations and/or confounding by family size in previous studies.
doi:10.1038/ijo.2013.189
PMCID: PMC4024316  PMID: 24097298
ALSPAC; birth order; blood pressure; body mass index; cardiovascular; obesity; Pelotas; siblings
2.  Maternal smoking and child psychological problems: Disentangling causal and non-causal effects 
Pediatrics  2010;126(1):e57-e65.
Objective
To explore associations of maternal prenatal smoking and child psychological problems and determine the role of causal intrauterine mechanisms.
Patients and Methods
Maternal smoking and child psychological problems were explored in 2 birth cohorts in Pelotas, Brazil (n=509; random sub-sample) and Avon Longitudinal Study of Parents and Children (ALSPAC), Britain (n=6,735). Four approaches for exploring causal mechanisms were applied: 1) cross-population comparisons between a high-income and a middle-income country, 2) multiple adjustment for socioeconomic and parental psychological factors, 3) maternal-paternal comparisons as a test of putative intrauterine effects; and 4) search for specific effects on different behavioural subscales.
Results
Socioeconomic patterning of maternal prenatal smoking was stronger in the ALSPAC compared with the Pelotas cohort. Despite this difference in a key confounder, consistency in observed associations was found between these cohorts. In both cohorts, unadjusted, maternal smoking was associated with greater offspring hyperactivity, conduct/externalizing problems, and peer problems, but not with emotional/internalizing problems. After adjusting for confounders and paternal prenatal smoking, only the association with conduct/externalizing problems persisted in both cohorts (conduct problems in the ALSPAC cohort, odds ratio OR: 1.24 [95% confidence interval (CI): 1.07–1.46], p= .005; externalizing problems in the Pelotas cohort, OR:1.82 [95% CI:1.19–2.78], p=.005; ORs reflect ordinal ORs of maternal smokers having offspring with higher scores). Maternal smoking associations were stronger than paternal smoking associations, although statistical evidence for differences was weak in 1 cohort.
Conclusions
Evidence from 4 approaches suggests a possible intrauterine effect of maternal smoking on offspring conduct/externalizing problems.
doi:10.1542/peds.2009-2754
PMCID: PMC3605780  PMID: 20587678
ALSPAC; Pelotas; prenatal smoking; child; behavioral problems; developmental origins
3.  Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight 
Freathy, Rachel M | Mook-Kanamori, Dennis O | Sovio, Ulla | Prokopenko, Inga | Timpson, Nicholas J | Berry, Diane J | Warrington, Nicole M | Widen, Elisabeth | Hottenga, Jouke Jan | Kaakinen, Marika | Lange, Leslie A | Bradfield, Jonathan P | Kerkhof, Marjan | Marsh, Julie A | Mägi, Reedik | Chen, Chih-Mei | Lyon, Helen N | Kirin, Mirna | Adair, Linda S | Aulchenko, Yurii S | Bennett, Amanda J | Borja, Judith B | Bouatia-Naji, Nabila | Charoen, Pimphen | Coin, Lachlan J M | Cousminer, Diana L | de Geus, Eco J. C. | Deloukas, Panos | Elliott, Paul | Evans, David M | Froguel, Philippe | Glaser, Beate | Groves, Christopher J | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hirschhorn, Joel N | Hofman, Albert | Holly, Jeff M P | Hyppönen, Elina | Kanoni, Stavroula | Knight, Bridget A | Laitinen, Jaana | Lindgren, Cecilia M | McArdle, Wendy L | O'Reilly, Paul F | Pennell, Craig E | Postma, Dirkje S | Pouta, Anneli | Ramasamy, Adaikalavan | Rayner, Nigel W | Ring, Susan M | Rivadeneira, Fernando | Shields, Beverley M | Strachan, David P | Surakka, Ida | Taanila, Anja | Tiesler, Carla | Uitterlinden, Andre G | van Duijn, Cornelia M | Wijga, Alet H | Willemsen, Gonneke | Zhang, Haitao | Zhao, Jianhua | Wilson, James F | Steegers, Eric A P | Hattersley, Andrew T | Eriksson, Johan G | Peltonen, Leena | Mohlke, Karen L | Grant, Struan F A | Hakonarson, Hakon | Koppelman, Gerard H | Dedoussis, George V | Heinrich, Joachim | Gillman, Matthew W | Palmer, Lyle J | Frayling, Timothy M | Boomsma, Dorret I | Smith, George Davey | Power, Chris | Jaddoe, Vincent W V | Jarvelin, Marjo-Riitta | McCarthy, Mark I
Nature genetics  2010;42(5):430-435.
INTRODUCTORY PARAGRAPH
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (N=10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in thirteen replication studies (N=27,591). Rs900400 near LEKR1 and CCNL1 (P=2×10−35), and rs9883204 in ADCY5 (P=7×10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and type 2 diabetes susceptibility,1 providing evidence that the well described association between lower birth weight and subsequent type 2 diabetes2,3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans with 4 birth weight-lowering alleles were, on average, 113g (95%CI 89-137g) lighter at birth than the 24% with 0 or 1 allele (Ptrend=7×10−30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.4
doi:10.1038/ng.567
PMCID: PMC2862164  PMID: 20372150
4.  Is there an intrauterine influence on obesity? Evidence from parent–child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC) 
Archives of Disease in Childhood  2007;92(10):876-880.
Background
It has been suggested that increasing obesity levels in young women lead to intrauterine environments that, in turn, stimulate increased obesity among their offspring, generating an intergenerational acceleration of obesity levels. If this mechanism is important, the association of maternal body mass index (BMI) with offspring BMI should be stronger than the association of paternal with offspring BMI.
Objective
To compare the relative strengths of association of maternal and paternal BMI with offspring BMI at age 7.5, taking into account the possible effect of non‐paternity.
Methods
We compared strength of association for maternal–offspring and paternal–offspring BMI for 4654 complete parent–offspring trios in the Avon Longitudinal Study of Parents and Children (ALSPAC), using unstandardised and standardised regression analysis. We carried out a sensitivity analysis to investigate the influence of non‐paternity on these associations.
Results
The strength of association between parental BMI and offspring BMI at age 7.5 was similar for both parents. Taking into account correlations between maternal and paternal BMI, performing standardised rather than unstandardised regression and carrying out a sensitivity analysis for non‐paternity emphasised the robustness of the general similarity of the associations. The associations between high parental BMI (top decile) and offspring BMI are also similar for both parents.
Conclusion
Comparison of mother–offspring and father–offspring associations for BMI suggests that intergenerational acceleration mechanisms do not make an important contribution to levels of childhood BMI within the population. Associations at later ages and for different components of body composition now require study.
doi:10.1136/adc.2006.104869
PMCID: PMC2083247  PMID: 17595200
5.  Change in sleep duration and type 2 diabetes: the Whitehall II study 
Diabetes care  2015;38(8):1467-1472.
Objective
Evidence suggests that short and long sleep are associated with a higher risk of type 2 diabetes. Using successive data waves spanning more than 20 years we examined whether a change in sleep duration is associated with incident diabetes.
Research Design and Methods
Sleep duration was reported at the beginning and end of four 5-year cycles: 1985-88 to 1991-94 (N=5613); 1991-94 to 1997-99 (N=4193); 1997-99 to 2002-04 (N=3840); 2002-04 to 2007-09 (N=4195). At each cycle, change in sleep duration was calculated for participants without diabetes. Incident diabetes at the end of the subsequent 5-year period was defined using: (1) fasting glucose; (2) 75g oral glucose tolerance test; and (3) glycated hemoglobin, in conjunction with diabetes medication and self-reported doctor diagnosis.
Results
Compared to the reference group of persistent 7-hour sleepers, an increase of ≥2hours sleep per night was associated with a higher risk of incident diabetes; Odds Ratios (95% Confidence Intervals) 1.65 (95% CI: 1.15, 2.37), in analyses adjusted for age, sex, employment grade and ethnic group. This association was partially attenuated by adjustment for body mass index and change in weight; 1.50 (1.04, 2.16). An increased risk of incident diabetes was also seen in persistent short sleepers (average ≤5.5 hours/night); 1.35 (1.04, 1.76), but this evidence weakened on adjustment for body mass index and change in weight; 1.25 (0.96, 1.63).
Conclusion
This study suggests that individuals whose sleep duration increases are at an increased risk of type 2 diabetes. Greater weight and weight gain in this group partly explain the association.
doi:10.2337/dc15-0186
PMCID: PMC4512137  PMID: 26068863
6.  Personal View 
BMJ : British Medical Journal  1991;303(6801):528.
PMCID: PMC1670811
7.  Genome-wide association study identifies 74 loci associated with educational attainment 
Okbay, Aysu | Beauchamp, Jonathan P. | Fontana, Mark A. | Lee, James J. | 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 | de Vlaming, Ronald | 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. | de Leeuw, Christiaan | 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. | 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 | Evans68, 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, 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. | Bultmann, 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 | Hinds, David A. | 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.
Nature  2016;533(7604):539-542.
Summary
Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease.
doi:10.1038/nature17671
PMCID: PMC4883595  PMID: 27225129
8.  Socioeconomic disparities in trajectories of adiposity across childhood 
Background
Socioeconomic inequalities in obesity are consistently observed in high-income countries. The development of such inequalities across childhood; however, has not been studied using longitudinal data.
Methods
Using data from the Avon Longitudinal Study of Parents and Children (participants were born 1991/2 in South-West England), we modelled trajectories of ponderal index (PI) (N=12 246) from birth to 2 years and body mass index (BMI) (N=11 380) from 2 to 10 years. Individual trajectories were estimated using mixed-effects models, and differences in trajectories by socioeconomic position (measured by maternal education) were investigated.
Results
There was little socioeconomic patterning of PI from birth to 2 years. Socioeconomic differences in BMI began to emerge by 4 years old, and widened with increasing age. Amongst girls there was a clear gradient across all categories of maternal education by age 8, with daughters of more educated women being less adipose. Amongst boys, sons of degree-educated women had lower BMI but there was little difference between the lower maternal education categories. By 10 years old the mean BMI difference between the highest and lowest maternal education category was 0.38 kg/m2 for boys and 0.89 kg/m2 for girls. The results imply that interventions to prevent inequalities in childhood obesity should begin in pre-school years.
doi:10.3109/17477166.2010.500387
PMCID: PMC5102325  PMID: 20860432
Child; longitudinal studies; obesity; socioeconomic factors; ALSPAC
9.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M L | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G | Fontana, Mark Alan | Meddens, S Fleur W | Linnér, Richard Karlsson | Rietveld, Cornelius A | Derringer, Jaime | Gratten, Jacob | Lee, James J | Liu, Jimmy Z | de Vlaming, Ronald | Ahluwalia, Tarunveer S | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C | Davies, Gail | Furlotte, Nicholas A | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J | Miller, Michael B | Lind, Penelope A | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Minica, Camelia C | Nolte, Ilja M | Mook-Kanamori, Dennis O | van der Most, Peter J | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Thorleifsson, Gudmar | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Bergmann, Sven | Bjornsdottir, Gyda | Boyle, Patricia A | Cherney, Samantha | Cox, Simon R | Davis, Oliver S P | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T | Fatemifar, Ghazaleh | Faul, Jessica D | Ferrucci, Luigi | Forstner, Andreas J | Gieger, Christian | Gupta, Richa | Harris, Tamara B | Harris, Juliette M | Holliday, Elizabeth G | Hottenga, Jouke-Jan | De Jager, Philip L | Kaakinen, Marika A | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J | Franke, Lude | Li-Gao, Ruifang | Liewald, David C | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W | Mosing, Miriam A | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J | Smith, Jennifer A | Sutin, Angelina R | Trzaskowski, Maciej | Vinkhuyzen, Anna E | Yu, Lei | Zabaneh, Delilah | Attia, John R | Bennett, David A | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J | van Duijn, Cornelia M | Eriksson, Johan G | Bültmann, Ute | de Geus, Eco J C | Groenen, Patrick J F | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A | Haworth, Claire M A | Hayward, Caroline | Heath, Andrew C | Hinds, David A | Hyppönen, Elina | Iacono, William G | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L R | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D | Lehtimäki, Terho | Magnusson, Patrik K E | Martin, Nicholas G | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J | Pasterkamp, Gerard | Pedersen, Nancy L | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S | Rosendaal, Frits R | den Ruijter, Hester M | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z | Sørensen, Thorkild I A | Spector, Tim D | Starr, John M | Stefansson, Kari | Steptoe, Andrew | Terracciano, Antonio | Thorsteinsdottir, Unnur | Thurik, A Roy | Timpson, Nicholas J | Tiemeier, Henning | Uitterlinden, André G | Vollenweider, Peter | Wagner, Gert G | Weir, David R | Yang, Jian | Conley, Dalton C | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I | Medland, Sarah E | Meyer, Michelle N | Pickrell, Joseph K | Esko, Tõnu | Krueger, Robert F | Beauchamp, Jonathan P | Koellinger, Philipp D | Benjamin, Daniel J | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
10.  Placental Size Is Associated Differentially With Postnatal Bone Size and Density 
Journal of Bone and Mineral Research  2016;31(10):1855-1864.
ABSTRACT
We investigated relationships between placental size and offspring adolescent bone indices using a population‐based, mother–offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual‐energy X‐ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z‐scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (β [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (β [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (β [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (β [95% CI]: –0.11 [–0.20, –0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2840
PMCID: PMC5010780  PMID: 26999363
OSTEOPOROSIS; EPIDEMIOLOGY; PLACENTA; BONE MASS; DXA; pQCT; ASLPAC
11.  Early Cannabis Use, Polygenic Risk Score for Schizophrenia, and Brain Maturation in Adolescence 
JAMA psychiatry  2015;72(10):1002-1011.
IMPORTANCE
Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure.
OBJECTIVE
To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12–21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014.
MAIN OUTCOMES AND MEASURES
Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score.
RESULTS
Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = −2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01–0.12]; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95% CI, 0.03–0.18]; P = .004).
CONCLUSIONS AND RELEVANCE
Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.
doi:10.1001/jamapsychiatry.2015.1131
PMCID: PMC5075969  PMID: 26308966
12.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M.L. | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G. | Fontana, Mark Alan | Meddens, S. Fleur W. | Linnér, Richard Karlsson | Rietveld, Cornelius A. | Derringer, Jaime | Gratten, Jacob | Lee, James J. | Liu, Jimmy Z. | de Vlaming, Ronald | Ahluwalia, Tarunveer S. | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C. | Furlotte, Nicholas A. | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R. | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W. | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J. | Lind, Penelope A. | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Miller, Michael B. | Minica, Camelia C. | Nolte, Ilja M. | Mook-Kanamori, Dennis | van der Most, Peter J. | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V. | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M. | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Boyle, Patricia A. | Cherney, Samantha | Cox, Simon R. | Davies, Gail | Davis, Oliver S.P. | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T. | Fatemifar, Ghazaleh | Faul, Jessica D. | Ferrucci, Luigi | Forstner, Andreas | Gieger, Christian | Gupta, Richa | Harris, Tamara B. | Harris, Juliette M. | Holliday, Elizabeth G. | Hottenga, Jouke-Jan | De Jager, Philip L. | Kaakinen, Marika A. | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J. | Franke, Lude | Li-Gao, Ruifang | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W. | Mosing, Miriam A. | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E. | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J. | Smith, Jennifer A. | Sutin, Angelina R. | Trzaskowski, Maciej | Vinkhuyzen, Anna E. | Yu, Lei | Zabaneh, Delilah | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I. | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J. | van Duijn, Cornelia M. | Eriksson, Johan G. | Bültmann, Ute | de Geus, Eco J.C. | Groenen, Patrick J.F. | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A. | Haworth, Claire M.A. | Hayward, Caroline | Heath, Andrew C. | Hinds, David A. | Hyppönen, Elina | Iacono, William G. | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J. | Pasterkamp, Gerard | Pedersen, Nancy L. | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S. | Rosendaal, Frits R. | den Ruijter, Hester M. | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z. | Sørensen, Thorkild I.A. | Spector, Tim D. | Steptoe, Andrew | Terracciano, Antonio | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Uitterlinden, André G. | Vollenweider, Peter | Wagner, Gert G. | Weir, David R. | Yang, Jian | Conley, Dalton C. | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Pickrell, Joseph K. | Esko, Tõnu | Krueger, Robert F. | Beauchamp, Jonathan P. | Koellinger, Philipp D. | Benjamin, Daniel J. | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
13.  Exaggerated Exercise Blood Pressure is Associated with Higher Left Ventricular Mass in Adolescence. The Avon Longitudinal Study of Parents and Children 
Journal of hypertension  2016;34(Suppl 1):e55.
Objective
Dynamic exercise results in an increase to systolic blood pressure (BP). Irrespective of resting BP, some individuals may experience an exaggerated rise in systolic BP with exercise, which in adulthood, is associated with greater risk of developing hypertension, cardiovascular morbidity and mortality. It is not known if exercise BP is associated with adverse cardiovascular risk during adolescence. We determined associations of exercise BP with left ventricular mass (LVM) in adolescents, with consideration of the possible confounding effect of body composition.
Design and method
We undertook a cross-sectional study of 3,949 adolescents (mean age 17.8 ± 0.4 years, 45% male) who were part of a UK population-based birth cohort study. A sub-maximal exercise step-test with automated BP measurement immediately post-exercise was completed and body composition (total fat and lean mass) assessed by dual-energy x-ray absorptiometry. A sub-sample (n = 1,241) underwent comprehensive echocardiographic assessment.
Results
Each 5 mmHg increase in post-exercise systolic BP was associated with 0.34 g/m2.7 (95% CI: 0.24, 0.45) greater LVM indexed to height2.7 with adjustment for age, sex and hypertension status (p < 0.001). Further adjustment for lean mass attenuated this association to 0.29 g/m2.7 (95% CI 0.19, 0.39; p < 0.001) for each 5 mmHg of post-exercise systolic BP, adjustment for fat mass attenuated it to 0.15 g/m2.7 (95% CI 0.05, 0.25; p = 0.003), and adjustment for both lean and fat mass attenuated it to 0.13 g/m2.7 (95% CI 0.03, 0.23; p = 0.012). Individuals with post-exercise systolic BP ≥150 mmHg (corresponding to post-exercise systolic BP >70th percentile) had a 7% greater LVM compared to those with post-exercise systolic BP < 150 mmHg (p < 0.001).
Conclusions
Exaggerated exercise systolic BP is associated with higher LVM, adjustment for body composition attenuates but does not abolish this association. These results may have important implications for cardiovascular risk in later life
doi:10.1097/01.hjh.0000499992.80444.b7
PMCID: PMC5051632  PMID: 27753917
14.  Psychological interventions for coronary heart disease 
Background
Psychological interventions can form part of comprehensive cardiac rehabilitation programmes (CCR). These interventions may include stress management interventions, which aim to reduce stress, either as an end in itself or to reduce risk for further cardiac events in patients with heart disease.
Objectives
To determine the effectiveness of psychological interventions, in particular stress management interventions, on mortality and morbidity, psychological measures, quality of life, and modifiable cardiac risk factors, in patients with coronary heart disease (CHD).
Search strategy
We searched CCTR to December 2001 (Issue 4, 2001), MEDLINE 1999 to December 2001 and EMBASE 1998 to the end of 2001, PsychINFO and CINAHL to December 2001. In addition, searches of reference lists of papers were made and expert advice was sought.
Selection criteria
RCTs of non-pharmacological psychological interventions, administered by trained staff, either single modality interventions or a part of CCR with minimum follow up of 6 months. Adults of all ages with CHD (prior myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina pectoris or coronary artery disease defined by angiography). Stress management (SM) trials were identified and reported in combination with other psychological interventions and separately.
Data collection and analysis
Studies were selected, and data were abstracted, independently by two reviewers. Authors were contacted where possible to obtain missing information.
Main results
Thirty six trials with 12,841 patients were included. Of these, 18 (5242 patients) were SM trials. Quality of many trials was poor with the majority not reporting adequate concealment of allocation, and only 6 blinded outcome assessors. Combining the results of all trials showed no strong evidence of effect on total or cardiac mortality, or revascularisation. There was a reduction in the number of non-fatal reinfarctions in the intervention group (OR 0.78 (0.67, 0.90), but the two largest trials (with 4809 patients randomized) were null for this outcome, and there was statistical evidence of publication bias. Similar results were seen for the SM subgroup of trials. Provision of any psychological intervention or SM intervention caused small reductions in anxiety and depression. Few trials reported modifiable cardiac risk factors or quality of life.
Authors’ conclusions
Overall psychological interventions showed no evidence of effect on total or cardiac mortality, but did show small reductions in anxiety and depression in patients with CHD. Similar results were seen for SM interventions when considered separately. However, the poor quality of trials, considerable heterogeneity observed between trials and evidence of significant publication bias make the pooled finding of a reduction in non-fatal myocardial infarction insecure.
doi:10.1002/14651858.CD002902.pub2
PMCID: PMC4170898  PMID: 15106183
*Psychotherapy; Coronary Disease [mortality; *psychology; rehabilitation]; Stress, Psychological [*therapy]; Humans
15.  Statins for the primary prevention of cardiovascular disease 
Background
Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear.
Objectives
To assess the effects, both harms and benefits, of statins in people with no history of CVD.
Search methods
To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions.
Selection criteria
Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included.
Data collection and analysis
Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated.
Main results
Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.84, 95% CI 0.73 to 0.96) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life.
Authors’ conclusions
Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of cancers or muscle pain among people without evidence of cardiovascular disease treated with statins. Other potential adverse events were not reported and some trials included people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.
doi:10.1002/14651858.CD004816.pub4
PMCID: PMC4164175  PMID: 21249663
Cardiovascular Diseases [blood; *prevention & control]; Cause of Death; Cholesterol, HDL [blood]; Cholesterol, LDL [blood]; Hydroxymethylglutaryl-CoA Reductase Inhibitors [adverse effects; *therapeutic use]; Primary Prevention; Randomized Controlled Trials as Topic; Adult; Humans
16.  Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population 
Nature genetics  2016;48(5):552-555.
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources (total n>38,000), we find genomewide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in an ASD or other neuropsychiatric disorder diagnosis. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
doi:10.1038/ng.3529
PMCID: PMC4986048  PMID: 26998691
17.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
Importance
Neonates born to overweight/obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.
Objective
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and obesity-related traits are causally related to offspring birth weight. Mendelian randomization makes use of the fact that genotypes are randomly determined at conception and are thus not confounded by non-genetic factors. Data were analysed on 30,487 women from 18 studies. Participants were of European ancestry from population- or community-based studies located in Europe, North America or Australia and participating in the Early Growth Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. We tested associations between a genetic score of 30 BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI and (ii) birth weight, to estimate the causal relationship between BMI and birth weight. Analyses were repeated for other obesity-related traits.
Exposures
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level, vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2 studies), from medical records (n= 10 studies) or from maternal report (n=6 studies).
Results
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per maternal BMI-raising allele (P=0.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele (P=7×10−14) and −4g (95%CI: −6, −2g) per SBP-raising allele (P=1×10−5), respectively. A 1 standard deviation (1 SD ≈ 4kg/m2) genetically higher maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth weight. A 1-SD genetically higher maternal fasting glucose (≈ 0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g) higher or −208g (95% CI: −394, −21g) lower birth weight, respectively. For BMI and fasting glucose these genetic associations were consistent with the observational associations, but for SBP, the genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with singleton offspring from 18 studies, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal systolic blood pressure was shown to be potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
doi:10.1001/jama.2016.1975
PMCID: PMC4811305  PMID: 26978208
18.  Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates☆ 
Economics and Human Biology  2014;13(100):99-106.
Highlights
•We model potential biases that may arise in Mendelian randomization analysis.•Genetic variants should robustly associate with exposures in independent samples.•If not, Mendelian randomization can suggest causality despite no true associations.
Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.
doi:10.1016/j.ehb.2013.12.002
PMCID: PMC3989031  PMID: 24388127
Smoking; Tobacco; Mendelian randomization; Causal inference; Instrumental variable
19.  Using genetic proxies for lifecourse sun exposure to assess the causal relationship of sun exposure with circulating vitamin D and prostate cancer risk 
Background
Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
Methods
We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
Results
The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit −0.27; 95%CI: −0.52, −0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders.
Conclusions
Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
Impact
The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
doi:10.1158/1055-9965.EPI-12-1248
PMCID: PMC3616836  PMID: 23441100
pigmentation; tanning; sun exposure; vitamin D; prostate cancer
20.  Common variants at 12q15 and 12q24 are associated with infant head circumference 
Taal, H Rob | Pourcain, Beate St | Thiering, Elisabeth | Das, Shikta | Mook-Kanamori, Dennis O | Warrington, Nicole M | Kaakinen, Marika | Kreiner-Møller, Eskil | Bradfield, Jonathan P | Freathy, Rachel M | Geller, Frank | Guxens, Mònica | Cousminer, Diana L | Kerkhof, Marjan | Timpson, Nicholas J | Ikram, M Arfan | Beilin, Lawrence J | Bønnelykke, Klaus | Buxton, Jessica L | Charoen, Pimphen | Chawes, Bo Lund Krogsgaard | Eriksson, Johan | Evans, David M | Hofman, Albert | Kemp, John P | Kim, Cecilia E | Klopp, Norman | Lahti, Jari | Lye, Stephen J | McMahon, George | Mentch, Frank D | Müller, Martina | O’Reilly, Paul F | Prokopenko, Inga | Rivadeneira, Fernando | Steegers, Eric A P | Sunyer, Jordi | Tiesler, Carla | Yaghootkar, Hanieh | Breteler, Monique M B | Debette, Stephanie | Fornage, Myriam | Gudnason, Vilmundur | Launer, Lenore J | van der Lugt, Aad | Mosley, Thomas H | Seshadri, Sudha | Smith, Albert V | Vernooij, Meike W | Blakemore, Alexandra IF | Chiavacci, Rosetta M | Feenstra, Bjarke | Fernandez-Benet, Julio | Grant, Struan F A | Hartikainen, Anna-Liisa | van der Heijden, Albert J | Iñiguez, Carmen | Lathrop, Mark | McArdle, Wendy L | Mølgaard, Anne | Newnham, John P | Palmer, Lyle J | Palotie, Aarno | Pouta, Annneli | Ring, Susan M | Sovio, Ulla | Standl, Marie | Uitterlinden, Andre G | Wichmann, H-Erich | Vissing, Nadja Hawwa | DeCarli, Charles | van Duijn, Cornelia M | McCarthy, Mark I | Koppelman, Gerard H. | Estivill, Xavier | Hattersley, Andrew T | Melbye, Mads | Bisgaard, Hans | Pennell, Craig E | Widen, Elisabeth | Hakonarson, Hakon | Smith, George Davey | Heinrich, Joachim | Jarvelin, Marjo-Riitta | Jaddoe, Vincent W V
Nature genetics  2012;44(5):532-538.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
doi:10.1038/ng.2238
PMCID: PMC3773913  PMID: 22504419
21.  The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study 
Scientific Reports  2016;6:31121.
Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m2) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10−3) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.
doi:10.1038/srep31121
PMCID: PMC4973233  PMID: 27487993
22.  Maternal Pre-pregnancy Overweight and Child Cognition and Behavior: Exploring Intrauterine Effects in Two Pregnancy Cohorts 
Pediatrics  2010;127(1):e202-e211.
Objective
Maternal greater pre-pregnancy adiposity has been associated with behavioral problems, such as ADHD, and lower intellectual function in offspring. However, few human studies have explored this and it is unclear if intrauterine mechanisms or confounding factors drive these associations.
Patients and Methods
Parental BMI and offspring verbal skills, non-verbal skills and behavioral problems were assessed in the British ALSPAC (N~5000) and Dutch Generation R (N~ 2500) cohorts. We aimed to determine the plausibility of intrauterine effects by (i) adjusting for multiple confounders, (ii) comparing associations between maternal and paternal BMI with offspring cognition/ behaviors, and (iii) searching for cross-cohort consistency.
Results
Maternal pre-pregnancy overweight was associated with reduced child verbal skills (unadjusted). However, after adjusting for confounders, this was not consistently observed in both cohorts. Maternal overweight was also associated with child total behavior problems and externalising problems, even after adjusting for confounders. However, this was observed in Generation R only and was not replicated in ALSPAC. No associations of maternal overweight with child attention problems, emotional/internalising problems, or non-verbal skills were observed in either cohort. Paternal overweight was not associated with any of the child outcomes, but was also less strongly related to potential confounding factors than was maternal overweight.
Conclusions
Overall, we find little consistent evidence of intrauterine effects of maternal pre-pregnancy overweight on child cognition and behavior. Some associations initially observed were not consistently replicated across cohorts or robust to adjustment for confounding factors and are thus likely to reflect confounding by socioeconomic or postnatal factors.
doi:10.1542/peds.2010-0651
PMCID: PMC3605781  PMID: 21187310
ALSPAC; behavioral problems; cognitive function; cohort; Generation R; intrauterine exposure; obesity; pregnancy
23.  The Association Between Irregular Menstruations and Acne With Asthma and Atopy Phenotypes 
American Journal of Epidemiology  2012;176(8):733-737.
Earlier menarche and irregular periods, among other markers of sex-hormone levels, have been associated with a higher risk of asthma and allergic diseases. This has suggested an etiologic role of sex hormones in the development of these conditions. The authors investigated the association of age at menarche, irregular periods, duration of menstruation, and acne with reported medical history of asthma and/or atopy (hay fever and/or eczema/urticaria) in a historical cohort of students born before the rise in asthma prevalence in the United Kingdom and attending university in 1948–1968. Finding consistent associations in a cohort that has experienced different life-course exposures and has different confounding structure can help to identify causal associations. In the Glasgow Alumni Cohort, irregular periods were associated with atopic asthma (multinomial odds ratio (MOR) = 2.79, 95% confidence interval (CI): 1.33, 5.83) and atopy alone (MOR = 1.40, 95% CI: 1.06, 1.84) but not with nonatopic asthma (MOR = 1.02, 95% CI: 0.45, 2.30), compared with students reporting no asthma and no atopy. The authors found no association with acne, a marker of high testosterone levels, that they hypothesized could point to polycystic ovary syndrome underpinning these associations. In summary, the authors found evidence for a potentially etiologic role of irregular menstruations with some specific asthma phenotypes, namely, atopic asthma and atopy, but not with nonatopic asthma.
doi:10.1093/aje/kws161
PMCID: PMC3472614  PMID: 23028012
acne; age at menarche; asthma; atopy; irregular menstruation
24.  Epigenome-wide Association Studies and the Interpretation of Disease -Omics 
PLoS Genetics  2016;12(6):e1006105.
Epigenome-wide association studies represent one means of applying genome-wide assays to identify molecular events that could be associated with human phenotypes. The epigenome is especially intriguing as a target for study, as epigenetic regulatory processes are, by definition, heritable from parent to daughter cells and are found to have transcriptional regulatory properties. As such, the epigenome is an attractive candidate for mediating long-term responses to cellular stimuli, such as environmental effects modifying disease risk. Such epigenomic studies represent a broader category of disease -omics, which suffer from multiple problems in design and execution that severely limit their interpretability. Here we define many of the problems with current epigenomic studies and propose solutions that can be applied to allow this and other disease -omics studies to achieve their potential for generating valuable insights.
doi:10.1371/journal.pgen.1006105
PMCID: PMC4919098  PMID: 27336614
25.  Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomisation Meta-Analysis in the CARTA Consortium 
Background
Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Methods and Results
Data on 141,317 participants (62,666 never, 40,669 former, 37,982 current smokers) from 23 population-based studies were included in observational and Mendelian randomisation (MR) meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure (SBP, DBP), hypertension, and resting heart rate. For the MR analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower SBP, DBP, and lower hypertension risk, but with higher resting heart rate. In observational analyses amongst current smokers, one cigarette/day higher level of smoking heaviness was associated with higher (0.21 beats/minute; 95% CI 0.19; 0.24) resting heart rate, and slightly higher DBP (0.05 mmHg; 95% CI 0.02; 0.08) and SBP (0.08 mmHg; 95% CI 0.03; 0.13). However, in MR analyses amongst current smokers, while each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 beats/minute/allele; 95% CI 0.18; 0.54), there was no strong association with DBP, SBP, or hypertension. This would suggest a 7 beats/minute higher heart rate in those who smoke 20 cigarettes/day.
Conclusions
This MR meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
doi:10.1161/CIRCGENETICS.115.001225
PMCID: PMC4684098  PMID: 26538566
blood pressure; hypertension; Mendelian randomization; heart rate; smoking

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