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1.  Association between Birth Characteristics and Cardiovascular Autonomic Function at Mid-Life 
PLoS ONE  2016;11(8):e0161604.
Low birth weight is associated with an increased risk of cardiovascular diseases in adulthood. As abnormal cardiac autonomic function is a common feature in cardiovascular diseases, we tested the hypothesis that low birth weight may also be associated with poorer cardiac autonomic function in middle-aged subjects.
At the age of 46, the subjects of the Northern Finland Birth Cohort 1966 were invited to examinations including questionnaires about health status and life style and measurement of vagally-mediated heart rate variability (rMSSD) from R-R intervals (RRi) and spontaneous baroreflex sensitivity (BRS) in both seated and standing positions. Maternal parameters had been collected in 1965–1966 since the 16th gestational week and birth variables immediately after delivery. For rMSSD, 1,799 men and 2,279 women without cardiorespiratory diseases and diabetes were included and 902 men and 1,020 women for BRS. The analyses were adjusted for maternal (age, anthropometry, socioeconomics, parity, gestational smoking) and adult variables (life style, anthropometry, blood pressure, glycemic and lipid status) potentially confounding the relationship between birth weight and autonomic function.
In men, birth weight correlated negatively with seated (r = -0.058, p = 0.014) and standing rMSSD (r = -0.090, p<0.001), as well as with standing BRS (r = -0.092, p = 0.006). These observations were verified using relevant birth weight categories (<2,500 g; 2,500–3,999 g; ≥4,000 g). In women, birth weight was positively correlated with seated BRS (r = 0.081, p = 0.010), but none of the other measures of cardiovascular autonomic function. These correlations remained significant after adjustment for potential confounders (p<0.05 for all).
In men, higher birth weight was independently associated with poorer cardiac autonomic function at mid-life. Same association was not observed in women. Our findings suggest that higher, not lower, birth weight in males may contribute to less favourable cardiovascular autonomic regulation and potentially to an elevated cardiovascular risk in later life.
PMCID: PMC4994955  PMID: 27552091
2.  Associations between pre-pregnancy obesity and asthma symptoms in adolescents 
The high prevalence of children's asthma symptoms, worldwide, is unexplained. We examined the relation between maternal pre-pregnancy weight and body mass index (BMI), and asthma symptoms in adolescents.
Data from 6945 adolescents born within the Northern Finland Birth Cohort 1986 were used. Prospective antenatal and birth outcome data, including maternal pre-pregnancy weight and BMI, and asthma symptoms in adolescent offspring at age 15–16 years, were employed. Logistic regression analyses were performed to examine the associations between relevant prenatal factors and asthma symptoms during adolescence.
Current wheeze (within the past year) was reported by 10.6% of adolescents, and physician-diagnosed asthma by 6.0%. High maternal pre-pregnancy BMI was a significant predictor of wheeze in the adolescents (increase per kilogram per square metre unit; 2.7%, 95% CI 0.9 to 4.4 for ever wheeze; 3.5%, 95% CI 1.3 to 5.8 for current wheeze), and adjusting for potential confounders further increased the risk (2.8%, 95% CI 0.5 to 5.1; 4.7%, 95% CI 1.9 to 7.7, respectively). High maternal pre-pregnancy weight, in the top tertile, also significantly increased the odds of current wheeze in the adolescent by 20% (95% CI 4 to 39), and adjusting for potential confounders further increased the risk (OR=1.52, 95% CI 1.19 to 1.95). Results were similar for current asthma. Furthermore, these significant associations were observed only among adolescents without parental history of atopy but not among those with parental history of atopy.
The association demonstrated here between maternal pre-pregnancy overweight and obesity, and asthma symptoms in adolescents suggests that increase in asthma may be partly related to the rapid rise in obesity in recent years.
PMCID: PMC3412048  PMID: 21844604
Asthma; wheeze; prevalence; adolescent; maternal pre-pregnancy weight; BMI; obesity
3.  Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior 
Thorgeirsson, Thorgeir E. | Gudbjartsson, Daniel F. | Surakka, Ida | Vink, Jacqueline M. | Amin, Najaf | Geller, Frank | Sulem, Patrick | Rafnar, Thorunn | Esko, Tõnu | Walter, Stefan | Gieger, Christian | Rawal, Rajesh | Mangino, Massimo | Prokopenko, Inga | Mägi, Reedik | Keskitalo, Kaisu | Gudjonsdottir, Iris H. | Gretarsdottir, Solveig | Stefansson, Hreinn | Thompson, John R. | Aulchenko, Yurii S. | Nelis, Mari | Aben, Katja K. | den Heijer, Martin | Dirksen, Asger | Ashraf, Haseem | Soranzo, Nicole | Valdes, Ana M | Steves, Claire | Uitterlinden, André G | Hofman, Albert | Tönjes, Anke | Kovacs, Peter | Hottenga, Jouke Jan | Willemsen, Gonneke | Vogelzangs, Nicole | Döring, Angela | Dahmen, Norbert | Nitz, Barbara | Pergadia, Michele L. | Saez, Berta | De Diego, Veronica | Lezcano, Victoria | Garcia-Prats, Maria D. | Ripatti, Samuli | Perola, Markus | Kettunen, Johannes | Hartikainen, Anna-Liisa | Pouta, Anneli | Laitinen, Jaana | Isohanni, Matti | Huei-Yi, Shen | Allen, Maxine | Krestyaninova, Maria | Hall, Alistair S | Jones, Gregory T. | van Rij, Andre M. | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Jonsson, Steinn | Matthiasson, Stefan E. | Oskarsson, Hogni | Tyrfingsson, Thorarinn | Kiemeney, Lambertus A. | Mayordomo, Jose I. | Lindholt, Jes S | Pedersen, Jesper Holst | Franklin, Wilbur A. | Wolf, Holly | Montgomery, Grant W. | Heath, Andrew C. | Martin, Nicholas G. | Madden, Pamela A.F. | Giegling, Ina | Rujescu, Dan | Järvelin, Marjo-Riitta | Salomaa, Veikko | Stumvoll, Michael | Spector, Tim D | Wichmann, H-Erich | Metspalu, Andres | Samani, Nilesh J. | Penninx, Brenda W. | Oostra, Ben A. | Boomsma, Dorret I. | Tiemeier, Henning | van Duijn, Cornelia M. | Kaprio, Jaakko | Gulcher, Jeffrey R. | McCarthy, Mark I. | Peltonen, Leena | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(5):448-453.
Smoking is a risk factor for most of the diseases leading in mortality1. We conducted genome-wide association (GWA) meta-analyses of smoking data within the ENGAGE consortium to search for common alleles associating with the number of cigarettes smoked per day (CPD) in smokers (N=31,266) and smoking initiation (N=46,481). We tested selected SNPs in a second stage (N=45,691 smokers), and assessed some in a third sample (N=9,040). Variants in three genomic regions associated with CPD (P< 5·10−8), including previously identified SNPs at 15q25 represented by rs1051730-A (0.80 CPD,P=2.4·10−69), and SNPs at 19q13 and 8p11, represented by rs4105144-C (0.39 CPD, P=2.2·10−12) and rs6474412-T (0.29 CPD,P= 1.4·10−8), respectively. Among the genes at the two novel loci, are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6), and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6) highlighted in previous studies of nicotine dependence2-3. Nominal associations with lung cancer were observed at both 8p11 (rs6474412-T,OR=1.09,P=0.04) and 19q13 (rs4105144-C,OR=1.12,P=0.0006).
PMCID: PMC3080600  PMID: 20418888
4.  Life-Course Analysis of a Fat Mass and Obesity-Associated (FTO) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling 
American Journal of Epidemiology  2010;172(6):653-665.
The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m)2) is well-replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well-established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI.
PMCID: PMC2938267  PMID: 20702506
body mass index; molecular epidemiology; structural equation model
5.  Early growth and adult respiratory function in men and women followed from the fetal period to adulthood 
Thorax  2006;62(5):396-402.
While some studies suggest that poor fetal growth rate, as indicated by lower birth weight, is associated with poor respiratory function in childhood, findings among adults remain inconsistent. A study was undertaken to determine the association between early growth and adult respiratory function.
A longitudinal birth cohort study was performed of 5390 men and women born full term and prospectively followed from the fetal period to adulthood. Weight at birth and infancy were recorded, and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were assessed by standard spirometry at age 31 years.
Adult FEV1 and FVC increased linearly with higher birth weight in both men and women with no apparent threshold. After adjustment for sex, adult height and other potential confounders operating through the life course, every 500 g higher birth weight was associated with a higher FEV1 of 53.1 ml (95% CI 38.4 to 67.7) and higher FVC of 52.5 ml (95% CI 35.5 to 69.4). These positive associations persisted across categories of smoking, physical activity and body mass index, with the lowest respiratory function noted among those with lower birth weight who were smokers, led a sedentary lifestyle or were overweight. Weight gain in infancy was also positively associated with adult lung function.
Birth weight is continuously and independently associated with adult respiratory function. It is plausible that poor growth in early life may restrict normal lung growth and development, which could have long‐term consequences on lung function later in life.
PMCID: PMC2117170  PMID: 17105780
6.  Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study 
Brain, Behavior, and Immunity  2017;59:253-259.
•This is one of the first longitudinal studies of serum CRP & subsequent schizophrenia.•Elevated serum CRP in adolescence is associated with risk of adult schizophrenia.•The CRP-schizophrenia association is consistent with a dose-response relationship.
Meta-analyses of cross-sectional studies confirm an increase in circulating inflammatory markers during acute psychosis. Longitudinal studies are scarce but are needed to understand whether elevated inflammatory markers are a cause or consequence of illness. We report a longitudinal study of serum C-reactive protein (CRP) in adolescence and subsequent risk of schizophrenia and related psychoses in adulthood in the Northern Finland Birth Cohort 1986.
Serum high-sensitivity CRP was measured at age 15/16 years in 6362 participants. ICD-10 diagnoses of schizophrenia and related psychoses were obtained from centralised hospital inpatient and outpatient registers up to age 27 years. Logistic regression calculated odds ratios (ORs) for psychotic outcomes associated with baseline CRP levels analysed as both continuous and categorical variables using American Heart Association criteria. Age, sex, body mass index, maternal education, smoking, and alcohol use were included as potential confounders.
By age 27 years, 88 cases of non-affective psychosis (1.38%), of which 22 were schizophrenia (0.35%), were identified. Adolescent CRP was associated with subsequent schizophrenia. The adjusted OR for schizophrenia by age 27 years for each standard deviation (SD) increase in CRP levels at age 15/16 years was 1.25 (95% CI, 1.07–1.46), which was consistent with a linear, dose-response relationship (P-value for quadratic term 0.23). Using CRP as a categorical variable, those with high (>3 mg/L) compared with low (<1 mg/L) CRP levels at baseline were more likely to develop schizophrenia; adjusted OR 4.25 (95% CI, 1.30–13.93). There was some indication that higher CRP was associated with earlier onset of schizophrenia (rs = −0.40; P = 0.07).
A longitudinal association between adolescent CRP levels and adult schizophrenia diagnosis indicates a potentially important role of inflammation in the pathogenesis of the illness, although the findings, based on a small number of cases, need to be interpreted with caution and require replication in other samples.
PMCID: PMC5176002  PMID: 27622678
CRP, C-reactive protein; OR, odds ratio; IL, interleukin; TNFα, tumour necrosis factor alpha; ALSPAC, Avon Longitudinal Study of Parents and Children; NFBC, Northern Finland Birth Cohort; AHA, American Heart Association; CDC, Centers for Disease Control and Prevention; FHDR, Finnish Hospital Discharge Register; ICD-10, International Classification of Diseases, 10th revision; NAPLS, North American Prodrome Longitudinal Study; C-reactive protein; Inflammatory markers; Systemic inflammation; Schizophrenia; Psychotic disorders; Adult; Adolescent; Longitudinal study
7.  Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence 
BMC Medicine  2016;14:205.
Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.
Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24–49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status.
Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters.
Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0733-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5153817  PMID: 27955712
Pregnancy; Trimesters; Postpartum; Metabolomics; Cytokines; Lipoprotein lipids; Fatty acids; Amino acids; Hormones; Inflammation; Metabolic networks
8.  Maternal and Child's Thyroid Function and Child's Intellect and Scholastic Performance 
Thyroid  2015;25(12):1363-1374.
Background: Maternal hypothyroidism and/or hypothyroxinemia have been associated with child's poor neuropsychological development, but the results have been inconsistent.
Methods: The Northern Finland Birth Cohort 1986 included all expected births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (M ± SD = 10.7 ± 2.8 weeks' gestation), and serum samples from their children were obtained at 16 years of age (n = 5829). All samples were analyzed for thyrotropin, free thyroxine (fT4), and thyroid peroxidase antibodies. The children's school performance was evaluated by their main teachers at eight years of age, as well as by the adolescents themselves at 16 years of age. Data on possible severe intellectual deficiency and mild cognitive limitation were collected from healthcare records and registries for all children. Logistic regression estimated the odds of poor school performance or severe intellectual deficiency/mild cognitive limitation associated with exposure to maternal thyroid dysfunction. The odds of poor school performance associated with the adolescents' own thyroid function at age 16 were also estimated. Results are presented as odds ratios (OR) with confidence intervals (CI), adjusted for maternal/family covariates and child's sex.
Results: Girls of mothers with subclinical hypothyroidism had more self-evaluated difficulties in mathematics than did girls of euthyroid mothers (OR 1.62 [CI 1.06–2.49]). Boys of hypothyroxinemic mothers repeated a school class more often than did boys of euthyroid mothers (OR 5.46 [CI 1.19–25.06]). Adolescents of hyperthyroid mothers had increased odds of poor self-evaluated performance in mathematics (OR 1.61 [CI 1.01–2.49]). Maternal thyroid dysfunction did not increase the odds of a child having severe intellectual deficiency/mild cognitive limitation. At 16 years of age, girls with hyperthyroidism by laboratory measurements had more difficulties in Finnish language (OR 2.82 [CI 1.42–5.61]) than did euthyroid girls. Boys with hypothyroxinemia by laboratory measurement had higher odds of having difficulties in Finnish and/or mathematics (OR 2.13 [CI 1.26–3.62]) than did euthyroid boys.
Conclusions: Maternal thyroid dysfunction during early pregnancy was associated with poorer scholastic performance of the adolescent. Additionally, adolescents' own thyroid dysfunction was associated with difficulties in school performance assessed by self-evaluation.
PMCID: PMC4684651  PMID: 26438036
9.  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.
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.
PMCID: PMC4883595  PMID: 27225129
10.  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.
PMCID: PMC4884152  PMID: 27089181
11.  Metabolic signatures of birthweight in 18 288 adolescents and adults 
Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults.
Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI).
Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood.
Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.
PMCID: PMC5100627  PMID: 27892411
Fetal programming; metabolic signatures; metabolomics; adiposity; fatty acids; amino acids
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.
PMCID: PMC4884152  PMID: 27089181
13.  Molecular mechanisms underlying variations in lung function: a systems genetics analysis 
The Lancet. Respiratory medicine  2015;3(10):782-795.
Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs.
The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature.
SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD.
The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico.
The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
PMCID: PMC5021067  PMID: 26404118
14.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
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.
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.
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).
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.
PMCID: PMC4811305  PMID: 26978208
15.  Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence 
Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood.
Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24–49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception.
Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery.
Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
PMCID: PMC5100613  PMID: 27538888
hormonal contraception; combined oral contraceptive pills; progestin-only contraceptives; metabolomics; cytokines; inflammation; amino acids; fatty acids; lipoproteins; hormones; risk factors
16.  Metabolic profiling of alcohol consumption in 9778 young adults 
Background: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults.
Methods: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24–45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays.
Results: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P < 0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R2 = 0.83, slope = 0.72 ± 0.04).
Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.
PMCID: PMC5100616  PMID: 27494945
Alcohol; risk factors; metabolomics; fatty acids; metabolic profiling
17.  Accelerometer-Measured Physical Activity and Sedentary Time Differ According to Education Level in Young Adults 
PLoS ONE  2016;11(7):e0158902.
This study examined the association of education level with objectively measured physical activity and sedentary time in young adults. Data from the Finnish ESTER study (2009–2011) (n = 538) was used to examine the association between educational attainment and different subcomponents of physical activity and sedentary time measured using hip-worn accelerometers (ActiGraph GT1M) for seven consecutive days. Overall physical activity, moderate-to-vigorous physical activity (MVPA), light-intensity physical activity and sedentary time were calculated separately for weekdays and weekend days. A latent profile analysis was conducted to identify the different profiles of sedentary time and the subcomponents of physical activity. The educational differences in accelerometer-measured physical activity and sedentary time varied according to the subcomponents of physical activity, and between weekdays and weekend days. A high education level was associated with high MVPA during weekdays and weekend days in both sexes, high sedentary time during weekdays in both sexes, and a low amount of light-intensity physical activity during weekdays in males and during weekdays and weekend days in females. The results indicate different challenges related to unhealthy behaviours in young adults with low and high education: low education is associated with a lack of MVPA, whereas high education is associated with a lack of light-intensity physical activity and high sedentary time especially during weekdays.
PMCID: PMC4942033  PMID: 27403958
18.  Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption 
Cornelis, Marilyn C | Byrne, Enda M | Esko, Tõnu | Nalls, Michael A | Ganna, Andrea | Paynter, Nina | Monda, Keri L | Amin, Najaf | Fischer, Krista | Renstrom, Frida | Ngwa, Julius S | Huikari, Ville | Cavadino, Alana | Nolte, Ilja M | Teumer, Alexander | Yu, Kai | Marques-Vidal, Pedro | Rawal, Rajesh | Manichaikul, Ani | Wojczynski, Mary K | Vink, Jacqueline M | Zhao, Jing Hua | Burlutsky, George | Lahti, Jari | Mikkilä, Vera | Lemaitre, Rozenn N | Eriksson, Joel | Musani, Solomon K | Tanaka, Toshiko | Geller, Frank | Luan, Jian’an | Hui, Jennie | Mägi, Reedik | Dimitriou, Maria | Garcia, Melissa E | Ho, Weang-Kee | Wright, Margaret J | Rose, Lynda M | Magnusson, Patrik KE | Pedersen, Nancy L | Couper, David | Oostra, Ben A | Hofman, Albert | Ikram, Mohammad Arfan | Tiemeier, Henning W | Uitterlinden, Andre G | van Rooij, Frank JA | Barroso, Inês | Johansson, Ingegerd | Xue, Luting | Kaakinen, Marika | Milani, Lili | Power, Chris | Snieder, Harold | Stolk, Ronald P | Baumeister, Sebastian E | Biffar, Reiner | Gu, Fangyi | Bastardot, François | Kutalik, Zoltán | Jacobs, David R | Forouhi, Nita G | Mihailov, Evelin | Lind, Lars | Lindgren, Cecilia | Michaëlsson, Karl | Morris, Andrew | Jensen, Majken | Khaw, Kay-Tee | Luben, Robert N | Wang, Jie Jin | Männistö, Satu | Perälä, Mia-Maria | Kähönen, Mika | Lehtimäki, Terho | Viikari, Jorma | Mozaffarian, Dariush | Mukamal, Kenneth | Psaty, Bruce M | Döring, Angela | Heath, Andrew C | Montgomery, Grant W | Dahmen, Norbert | Carithers, Teresa | Tucker, Katherine L | Ferrucci, Luigi | Boyd, Heather A | Melbye, Mads | Treur, Jorien L | Mellström, Dan | Hottenga, Jouke Jan | Prokopenko, Inga | Tönjes, Anke | Deloukas, Panos | Kanoni, Stavroula | Lorentzon, Mattias | Houston, Denise K | Liu, Yongmei | Danesh, John | Rasheed, Asif | Mason, Marc A | Zonderman, Alan B | Franke, Lude | Kristal, Bruce S | Karjalainen, Juha | Reed, Danielle R | Westra, Harm-Jan | Evans, Michele K | Saleheen, Danish | Harris, Tamara B | Dedoussis, George | Curhan, Gary | Stumvoll, Michael | Beilby, John | Pasquale, Louis R | Feenstra, Bjarke | Bandinelli, Stefania | Ordovas, Jose M | Chan, Andrew T | Peters, Ulrike | Ohlsson, Claes | Gieger, Christian | Martin, Nicholas G | Waldenberger, Melanie | Siscovick, David S | Raitakari, Olli | Eriksson, Johan G | Mitchell, Paul | Hunter, David J | Kraft, Peter | Rimm, Eric B | Boomsma, Dorret I | Borecki, Ingrid B | Loos, Ruth JF | Wareham, Nicholas J | Vollenweider, Peter | Caporaso, Neil | Grabe, Hans Jörgen | Neuhouser, Marian L | Wolffenbuttel, Bruce HR | Hu, Frank B | Hyppönen, Elina | Järvelin, Marjo-Riitta | Cupples, L Adrienne | Franks, Paul W | Ridker, Paul M | van Duijn, Cornelia M | Heiss, Gerardo | Metspalu, Andres | North, Kari E | Ingelsson, Erik | Nettleton, Jennifer A | van Dam, Rob M | Chasman, Daniel I
Molecular psychiatry  2014;20(5):647-656.
PMCID: PMC4388784  PMID: 25288136
19.  Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors 
Fall, Tove | Hägg, Sara | Ploner, Alexander | Mägi, Reedik | Fischer, Krista | Draisma, Harmen H.M. | Sarin, Antti-Pekka | Benyamin, Beben | Ladenvall, Claes | Åkerlund, Mikael | Kals, Mart | Esko, Tõnu | Nelson, Christopher P. | Kaakinen, Marika | Huikari, Ville | Mangino, Massimo | Meirhaeghe, Aline | Kristiansson, Kati | Nuotio, Marja-Liisa | Kobl, Michael | Grallert, Harald | Dehghan, Abbas | Kuningas, Maris | de Vries, Paul S. | de Bruijn, Renée F.A.G. | Willems, Sara M. | Heikkilä, Kauko | Silventoinen, Karri | Pietiläinen, Kirsi H. | Legry, Vanessa | Giedraitis, Vilmantas | Goumidi, Louisa | Syvänen, Ann-Christine | Strauch, Konstantin | Koenig, Wolfgang | Lichtner, Peter | Herder, Christian | Palotie, Aarno | Menni, Cristina | Uitterlinden, André G. | Kuulasmaa, Kari | Havulinna, Aki S. | Moreno, Luis A. | Gonzalez-Gross, Marcela | Evans, Alun | Tregouet, David-Alexandre | Yarnell, John W.G. | Virtamo, Jarmo | Ferrières, Jean | Veronesi, Giovanni | Perola, Markus | Arveiler, Dominique | Brambilla, Paolo | Lind, Lars | Kaprio, Jaakko | Hofman, Albert | Stricker, Bruno H. | van Duijn, Cornelia M. | Ikram, M. Arfan | Franco, Oscar H. | Cottel, Dominique | Dallongeville, Jean | Hall, Alistair S. | Jula, Antti | Tobin, Martin D. | Penninx, Brenda W. | Peters, Annette | Gieger, Christian | Samani, Nilesh J. | Montgomery, Grant W. | Whitfield, John B. | Martin, Nicholas G. | Groop, Leif | Spector, Tim D. | Magnusson, Patrik K. | Amouyel, Philippe | Boomsma, Dorret I. | Nilsson, Peter M. | Järvelin, Marjo-Riitta | Lyssenko, Valeriya | Metspalu, Andres | Strachan, David P. | Salomaa, Veikko | Ripatti, Samuli | Pedersen, Nancy L. | Prokopenko, Inga | McCarthy, Mark I. | Ingelsson, Erik
Diabetes  2015;64(5):1841-1852.
Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
PMCID: PMC4407863  PMID: 25712996
20.  Adiposity as a cause of cardiovascular disease: a Mendelian randomization study 
Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.
Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.
Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.
Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.
PMCID: PMC4553708  PMID: 26016847
Cardiovascular disease; epidemiology; body mass index; Mendelian randomization
21.  Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA 
Nature Communications  2016;7:11122.
Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.
Circulating metabolites reflect human health and disease. Here, Kettunen et al. perform a genome-wide association study on 123 circulating metabolic traits and identify novel genetic loci influencing systemic metabolism. They also link new molecular pathways with a known cardiovascular risk factor Lp(a).
PMCID: PMC4814583  PMID: 27005778
22.  Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase 
Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized.
This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways.
Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts.
Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03).
Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.
PMCID: PMC4783625  PMID: 26965542
cholesterol lowering; drug development; lipoproteins; Mendelian randomization; metabolomics; CVD, cardiovascular disease; HDL, high-density lipoprotein; HMGCR, HMG-CoA reductase; IDL, intermediate-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; NMR, nuclear magnetic resonance; VLDL, very-low-density lipoprotein
23.  Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas 
Human Genetics  2016;135:425-439.
Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-016-1638-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4796339  PMID: 26899160
24.  metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis 
Bioinformatics  2016;32(13):1981-1989.
Motivation: A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests.
Results: We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.
Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies.
Availability and implementation: Code is available at
Contacts: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4920109  PMID: 27153689
25.  The impact of low-frequency and rare variants on lipid levels 
Surakka, Ida | Horikoshi, Momoko | Mägi, Reedik | Sarin, Antti-Pekka | Mahajan, Anubha | Lagou, Vasiliki | Marullo, Letizia | Ferreira, Teresa | Miraglio, Benjamin | Timonen, Sanna | Kettunen, Johannes | Pirinen, Matti | Karjalainen, Juha | Thorleifsson, Gudmar | Hägg, Sara | Hottenga, Jouke-Jan | Isaacs, Aaron | Ladenvall, Claes | Beekman, Marian | Esko, Tõnu | Ried, Janina S | Nelson, Christopher P | Willenborg, Christina | Gustafsson, Stefan | Westra, Harm-Jan | Blades, Matthew | de Craen, Anton JM | de Geus, Eco J | Deelen, Joris | Grallert, Harald | Hamsten, Anders | Havulinna, Aki S. | Hengstenberg, Christian | Houwing-Duistermaat, Jeanine J | Hyppönen, Elina | Karssen, Lennart C | Lehtimäki, Terho | Lyssenko, Valeriya | Magnusson, Patrik KE | Mihailov, Evelin | Müller-Nurasyid, Martina | Mpindi, John-Patrick | Pedersen, Nancy L | Penninx, Brenda WJH | Perola, Markus | Pers, Tune H | Peters, Annette | Rung, Johan | Smit, Johannes H | Steinthorsdottir, Valgerdur | Tobin, Martin D | Tsernikova, Natalia | van Leeuwen, Elisabeth M | Viikari, Jorma S | Willems, Sara M | Willemsen, Gonneke | Schunkert, Heribert | Erdmann, Jeanette | Samani, Nilesh J | Kaprio, Jaakko | Lind, Lars | Gieger, Christian | Metspalu, Andres | Slagboom, P Eline | Groop, Leif | van Duijn, Cornelia M | Eriksson, Johan G | Jula, Antti | Salomaa, Veikko | Boomsma, Dorret I | Power, Christine | Raitakari, Olli T | Ingelsson, Erik | Järvelin, Marjo-Riitta | Stefansson, Kari | Franke, Lude | Ikonen, Elina | Kallioniemi, Olli | Pietiäinen, Vilja | Lindgren, Cecilia M | Thorsteinsdottir, Unnur | Palotie, Aarno | McCarthy, Mark I | Morris, Andrew P | Prokopenko, Inga | Ripatti, Samuli
Nature genetics  2015;47(6):589-597.
Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes imputation in 62,166 samples, we identify association to lipids in 93 loci including 79 previously identified loci with new lead-SNPs, 10 new loci, 15 loci with a low-frequency and 10 loci with missense lead-SNPs, and, 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC, and APOE), or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2), explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for LDL-C and TC. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to re-sequencing.
PMCID: PMC4757735  PMID: 25961943

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