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Your search keyword '"Kaprio, Jaakko"' showing total 113 results
113 results on '"Kaprio, Jaakko"'

1. Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Author

van der Kolk BW, Saari S, Lovric A, Arif M, Alvarez M, Ko A, Miao Z, Sahebekhtiari N, Muniandy M, Heinonen S, Oghabian A, Jokinen R, Jukarainen S, Hakkarainen A, Lundbom J, Kuula J, Groop PH, Tukiainen T, Lundbom N, Rissanen A, Kaprio J, Williams EG, Zamboni N, Mardinoglu A, Pajukanta P, and Pietiläinen KH

Subjects
Adipocytes metabolism, Inflammation metabolism, Insulin Resistance physiology, Mitochondria metabolism, Muscle, Skeletal pathology, Subcutaneous Fat metabolism, Twins, Monozygotic genetics, Adipose Tissue metabolism, Body Mass Index, Muscle, Skeletal metabolism, Obesity metabolism
Abstract

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Published
2021
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2. A higher glycemic response to oral glucose is associated with higher plasma apolipoprotein C3 independently of BMI in healthy twins.

Author

Bozzetto L, Berntzen BJ, Kaprio J, Rissanen A, Taskinen MR, and Pietiläinen KH

Subjects
Adiposity, Adult, Biomarkers blood, Female, Finland, Glucose Metabolism Disorders diagnosis, Glucose Metabolism Disorders genetics, Glucose Metabolism Disorders physiopathology, Healthy Volunteers, Humans, Male, Obesity diagnosis, Obesity genetics, Obesity physiopathology, Risk Factors, Time Factors, Triglycerides blood, Twins, Monozygotic genetics, Young Adult, Apolipoprotein C-III blood, Blood Glucose metabolism, Body Mass Index, Glucose Metabolism Disorders blood, Glucose Tolerance Test, Obesity blood
Abstract

Background and Aims: Plasma apolipoprotein C3 (ApoC3) is associated with higher plasma triglyceride and type 2 diabetes incidence. We evaluated whether body mass index (BMI) or glucose metabolism were associated with ApoC3 in healthy monozygotic (MZ) twins., Methods and Results: Forty-seven MZ twin-pairs (20 man, 27 women), aged 23-42 years, were divided in subgroups according to discordance or concordance for (a) BMI (within-pair difference (Δ) in BMI≥3.0 or<3.0 kg/m 2 ), or (b) 2-h glucose iAUC, during oral glucose tolerance test (ΔGlucose iAUC ≥97.5 or<97.5 mmol × 120 minutes). Within these discordant or concordant subgroups, we tested (Wilcoxon signed-rank test) co-twin differences in ApoC3, adiposity measures, insulin-resistance and beta-cell function indices, and plasma and lipoprotein lipids. In BMI-Discordant (p = 0.92) or BMI-Concordant (p = 0.99) subgroups, ApoC3 did not differ between leaner and heavier co-twins. In the Glucose-Discordant subgroup, ApoC3 was significantly higher in twins with higher Glucose iAUC than in their co-twins with the lower Glucose iAUC (10.03 ± 0.78 vs. 8.48 ± 0.52 mg/dl; M ± SE; p = 0.032). Co-twins with higher Glucose iAUC also had higher waist circumference, body fat percentage, liver fat content, worse insulin-sensitivity and beta-cell function and higher cholesterol and triglyceride in plasma VLDL, IDL, and LDL. In Glucose-Concordant twin-pairs, no significant differences were observed in the explored variables. In all twin-pairs, ΔApoC3 correlated with Δ in lipids and glucose metabolism variables, the closest relationship being between ΔApoC3 and ΔVLDL triglyceride (r = 0.74, p < 0.0001)., Conclusions: While ApoC3 was not related to acquired differences in BMI, it associated with early dysregulation of glucose metabolism independently of obesity and genetic background., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest associated with this manuscript., (Copyright © 2019. Published by Elsevier B.V.)

Published
2020
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3. Associations of sitting time with leisure-time physical inactivity, education, and body mass index change.

Author

Piirtola M, Kaprio J, Svedberg P, Silventoinen K, and Ropponen A

Subjects
Aged, Employment, Female, Finland, Humans, Longitudinal Studies, Male, Middle Aged, Self Report, Sitting Position, Surveys and Questionnaires, Time Factors, Weight Gain, Body Mass Index, Educational Status, Leisure Activities, Sedentary Behavior
Abstract

We aimed to investigate the associations of long-term leisure-time physical inactivity, body mass index (BMI) change, and education with sitting time in a 35-year follow-up based on self-reports in surveys. Influences of working status in 2011 and familial confounding on the associations were tested. Data were based on the population-based Finnish Twin Cohort of 5232 twins (53-67-year-old, 41% men) with four surveys in 1975-2011. Statistical analyses were performed using linear regression with several covariates. The effect of familial confounding (genetics and shared environment) was analyzed using a co-twin control design which should be interpreted as if familial confounding plays a role, an association should be seen among all individuals but not in discordant twin pairs. Compared to those not at work, those at work had a longer total sitting time/d. For those at work, higher education was associated with more total sitting but with less non-work sitting. Long-term leisure-time physical inactivity was associated with more non-work sitting among those at work, whereas long-term weight gain with more total and non-work sitting regardless of working status. Familial confounding attenuated the associations, except for the association of increasing BMI with total and non-work sitting among women at work. To conclude, total sitting time was longer among those still at work, but it was also influenced by long-term leisure-time physical inactivity, higher education, and an increase of BMI over the years. Public health efforts should be targeted to reduce sedentary behavior by promoting life-long leisure-time physical activity and weight control., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2020
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4. Eating Behaviors in Healthy Young Adult Twin Pairs Discordant for Body Mass Index.

Author

Berntzen BJ, Jukarainen S, Bogl LH, Rissanen A, Kaprio J, and Pietiläinen KH

Subjects
Adult, Female, Humans, Male, Obesity physiopathology, Twins, Dizygotic genetics, Twins, Monozygotic genetics, Young Adult, Body Mass Index, Eating genetics, Feeding Behavior physiology, Obesity genetics
Abstract

We aimed to study the eating behavioral traits that associate with body mass index (BMI) among BMI-discordant twin pairs. This cross-sectional study examined self-reported eating behaviors in 134 healthy young adult twin pairs (57 monozygotic [MZ] and 77 same-sex dizygotic [DZ]), of whom 29 MZ and 46 DZ pairs were BMI discordant (BMI difference ≥ 3 kg/m2). In both MZ and DZ BMI-discordant pairs, the heavier co-twins reported being less capable of regulating their food intake optimally than their leaner co-twins, mainly due to 'frequent overeating'. Furthermore, the heavier co-twins reported augmented 'disinhibited eating', 'binge-eating scores' and 'body dissatisfaction'. The twins agreed more frequently that the heavier co-twins (rather than the leaner co-twins) ate more food in general, and more fatty food, in particular. No significant behavioral differences emerged in BMI-concordant twin pairs. Overeating - measured by 'frequent overeating', 'disinhibited eating' and 'binge-eating score' - was the main behavioral trait associated with higher BMI, independent of genotype and shared environment.

Published
2019
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5. Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs.

Author

Sahebekhtiari N, Saraswat M, Joenväärä S, Jokinen R, Lovric A, Kaye S, Mardinoglu A, Rissanen A, Kaprio J, Renkonen R, and Pietiläinen KH

Subjects
Adult, Female, Humans, Male, Body Mass Index, Complement System Proteins metabolism, Insulin Resistance, Obesity blood, Twins, Monozygotic
Abstract

Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation., Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m -2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy., Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids., Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2019
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6. Parental Education and Genetics of BMI from Infancy to Old Age: A Pooled Analysis of 29 Twin Cohorts.

Author

Silventoinen K, Jelenkovic A, Latvala A, Yokoyama Y, Sund R, Sugawara M, Tanaka M, Matsumoto S, Aaltonen S, Piirtola M, Freitas DL, Maia JA, Öncel SY, Aliev F, Ji F, Ning F, Pang Z, Rebato E, Saudino KJ, Cutler TL, Hopper JL, Ullemar V, Almqvist C, Magnusson PKE, Cozen W, Hwang AE, Mack TM, Willemsen G, Bartels M, van Beijsterveldt CEM, Nelson TL, Whitfield KE, Sung J, Kim J, Lee J, Lee S, Llewellyn CH, Fisher A, Medda E, Nisticò L, Toccaceli V, Baker LA, Tuvblad C, Corley RP, Huibregtse BM, Derom CA, Vlietinck RF, Loos RJF, Knafo-Noam A, Mankuta D, Abramson L, Burt SA, Klump KL, Silberg JL, Maes HH, Krueger RF, McGue M, Pahlen S, Gatz M, Butler DA, Harris JR, Nilsen TS, Harden KP, Tucker-Drob EM, Franz CE, Kremen WS, Lyons MJ, Lichtenstein P, Jeong HU, Hur YM, Boomsma DI, Sørensen TIA, and Kaprio J

Subjects
Adolescent, Adult, Aged, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Middle Aged, Twins, Young Adult, Body Mass Index, Gene-Environment Interaction, Parents education
Abstract

Objective: The objective of this study was to analyze how parental education modifies the genetic and environmental variances of BMI from infancy to old age in three geographic-cultural regions., Methods: A pooled sample of 29 cohorts including 143,499 twin individuals with information on parental education and BMI from age 1 to 79 years (299,201 BMI measures) was analyzed by genetic twin modeling., Results: Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education level was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education levels. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low education level category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia., Conclusions: Lower parental education level is associated with higher mean BMI and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay among genetic predisposition, childhood social environment, and macro-social context is important for socioeconomic differences in BMI., (© 2019 The Obesity Society.)

Published
2019
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7. Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

Author

Gielen M, Hageman GJ, Antoniou EE, Nordfjall K, Mangino M, Balasubramanyam M, de Meyer T, Hendricks AE, Giltay EJ, Hunt SC, Nettleton JA, Salpea KD, Diaz VA, Farzaneh-Far R, Atzmon G, Harris SE, Hou L, Gilley D, Hovatta I, Kark JD, Nassar H, Kurz DJ, Mather KA, Willeit P, Zheng YL, Pavanello S, Demerath EW, Rode L, Bunout D, Steptoe A, Boardman L, Marti A, Needham B, Zheng W, Ramsey-Goldman R, Pellatt AJ, Kaprio J, Hofmann JN, Gieger C, Paolisso G, Hjelmborg JBH, Mirabello L, Seeman T, Wong J, van der Harst P, Broer L, Kronenberg F, Kollerits B, Strandberg T, Eisenberg DTA, Duggan C, Verhoeven JE, Schaakxs R, Zannolli R, Dos Reis RMR, Charchar FJ, Tomaszewski M, Mons U, Demuth I, Iglesias Molli AE, Cheng G, Krasnienkov D, D'Antono B, Kasielski M, McDonnell BJ, Ebstein RP, Sundquist K, Pare G, Chong M, and Zeegers MP

Subjects
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cross-Sectional Studies, Ethnicity, Humans, Leukocytes ultrastructure, Male, Middle Aged, Obesity pathology, Sex Factors, Body Mass Index, Telomere ultrastructure, Telomere Shortening physiology
Abstract

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes., Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span., Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity., Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed., Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

Published
2018
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8. Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

Author

Piirtola M, Jelenkovic A, Latvala A, Sund R, Honda C, Inui F, Watanabe M, Tomizawa R, Iwatani Y, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Tarnoki AD, Tarnoki DL, Martin NG, Montgomery GW, Medland SE, Rasmussen F, Tynelius P, Tan Q, Zhang D, Pang Z, Rebato E, Stazi MA, Fagnani C, Brescianini S, Busjahn A, Harris JR, Brandt I, Nilsen TS, Cutler TL, Hopper JL, Corley RP, Huibregtse BM, Sung J, Kim J, Lee J, Lee S, Gatz M, Butler DA, Franz CE, Kremen WS, Lyons MJ, Magnusson PKE, Pedersen NL, Dahl Aslan AK, Öncel SY, Aliev F, Derom CA, Vlietinck RF, Loos RJF, Silberg JL, Maes HH, Boomsma DI, Sørensen TIA, Korhonen T, Kaprio J, and Silventoinen K

Subjects
Adolescent, Adult, Aged, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Smoking genetics, Smoking Cessation, Young Adult, Body Mass Index, Smoking adverse effects, Smoking pathology, Twins, Dizygotic, Twins, Monozygotic
Abstract

Background: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background., Methods and Findings: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade., Conclusions: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2., Competing Interests: TK reports personal consultation fees from Pfizer Finland, during the conduct of the study but outside of this study. JK reports grants from the Academy of Finland and the Sigrid Juselius Foundation, during the conduct of the study, and personal fees from Pfizer Inc., outside the submitted study. AB reports working in the HealthTwiSt GmbH but the company did not have any impact on this study. FI reports grants from JSPS KAKENHI JP (23593419,16K15978), during the conduct of the study. MG reports grants from the National Institutes of Health, during the conduct of the study, and other grants from National Institutes of Health, outside the submitted work period. All other authors have nothing to declare. None of the funders played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. None of the commercial affiliations affects our adherence to PLOS ONE policies on sharing data and materials. The specific roles of authors with commercial affiliations (AB, JK, TK) are articulated in the 'author contributions' section. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the paper for publication.

Published
2018
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9. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals.

Author

Kivimäki M, Luukkonen R, Batty GD, Ferrie JE, Pentti J, Nyberg ST, Shipley MJ, Alfredsson L, Fransson EI, Goldberg M, Knutsson A, Koskenvuo M, Kuosma E, Nordin M, Suominen SB, Theorell T, Vuoksimaa E, Westerholm P, Westerlund H, Zins M, Kivipelto M, Vahtera J, Kaprio J, Singh-Manoux A, and Jokela M

Subjects
Aged, Cohort Studies, Female, Global Health, Humans, Male, Middle Aged, Risk Factors, Time Factors, Weight Loss physiology, Body Mass Index, Data Interpretation, Statistical, Dementia etiology, Obesity complications
Abstract

Introduction: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects., Methods: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis., Results: Hazard ratios per 5-kg/m 2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis., Conclusions: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2018
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10. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Author

Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Corominas Galbany J, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Di Angelantonio E, Drenos F, Du M, Dubé MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland Ø, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jørgensen ME, Jørgensen T, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikäinen LP, Männistö S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Olde Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renström F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Velez Edwards DR, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Völker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhao W, Zhou W, Zondervan KT, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, and Loos RJF

Subjects
Adult, Animals, Drosophila genetics, Female, Gene Frequency, Humans, Male, Proteins genetics, Syndrome, Body Mass Index, Energy Intake genetics, Energy Metabolism genetics, Genetic Variation, Obesity genetics
Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Published
2018
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11. Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project.

Author

Jelenkovic A, Yokoyama Y, Sund R, Pietiläinen KH, Hur YM, Willemsen G, Bartels M, van Beijsterveldt TCEM, Ooki S, Saudino KJ, Stazi MA, Fagnani C, D'Ippolito C, Nelson TL, Whitfield KE, Knafo-Noam A, Mankuta D, Abramson L, Heikkilä K, Cutler TL, Hopper JL, Wardle J, Llewellyn CH, Fisher A, Corley RP, Huibregtse BM, Derom CA, Vlietinck RF, Loos RJF, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Tarnoki AD, Tarnoki DL, Burt SA, Klump KL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Dubois L, Boivin M, Brendgen M, Dionne G, Vitaro F, Harris JR, Brandt I, Nilsen TS, Craig JM, Saffery R, Rasmussen F, Tynelius P, Bayasgalan G, Narandalai D, Haworth CMA, Plomin R, Ji F, Ning F, Pang Z, Rebato E, Krueger RF, McGue M, Pahlen S, Boomsma DI, Sørensen TIA, Kaprio J, and Silventoinen K

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Internationality, Linear Models, Male, Middle Aged, Twins, Dizygotic, Twins, Monozygotic, Young Adult, Birth Weight genetics, Body Mass Index
Abstract

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors., Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses., Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m2 higher BMI (P < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m2 per kg birthweight, P < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood., Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Published
2017
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12. Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts.

Author

Silventoinen K, Jelenkovic A, Sund R, Yokoyama Y, Hur YM, Cozen W, Hwang AE, Mack TM, Honda C, Inui F, Iwatani Y, Watanabe M, Tomizawa R, Pietiläinen KH, Rissanen A, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Tan Q, Zhang D, Pang Z, Piirtola M, Aaltonen S, Öncel SY, Aliev F, Rebato E, Hjelmborg JB, Christensen K, Skytthe A, Kyvik KO, Silberg JL, Eaves LJ, Cutler TL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Song YM, Yang S, Lee K, Franz CE, Kremen WS, Lyons MJ, Busjahn A, Nelson TL, Whitfield KE, Kandler C, Jang KL, Gatz M, Butler DA, Stazi MA, Fagnani C, D'Ippolito C, Duncan GE, Buchwald D, Martin NG, Medland SE, Montgomery GW, Jeong HU, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Dahl Aslan AK, McAdams TA, Eley TC, Gregory AM, Tynelius P, Baker LA, Tuvblad C, Bayasgalan G, Narandalai D, Spector TD, Mangino M, Lachance G, Burt SA, Klump KL, Harris JR, Brandt I, Nilsen TS, Krueger RF, McGue M, Pahlen S, Corley RP, Huibregtse BM, Bartels M, van Beijsterveldt CE, Willemsen G, Goldberg JH, Rasmussen F, Tarnoki AD, Tarnoki DL, Derom CA, Vlietinck RF, Loos RJ, Hopper JL, Sung J, Maes HH, Turkheimer E, Boomsma DI, Sørensen TI, and Kaprio J

Subjects
Adult, Age Factors, Aged, Aged, 80 and over, Australia, Culture, Europe, Female, Humans, Male, Middle Aged, North America, Prevalence, Sex Factors, Twins, Dizygotic genetics, Twins, Monozygotic genetics, Young Adult, Body Mass Index, Body Weight genetics, Environment, Gene-Environment Interaction, Obesity genetics, Quantitative Trait, Heritable
Abstract

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

Published
2017
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13. The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models.

Author

Wolters M, Dering C, Siani A, Russo P, Kaprio J, Risé P, Moreno LA, De Henauw S, Mehlig K, Veidebaum T, Molnár D, Tornaritis M, Iacoviello L, Pitsiladis Y, Galli C, Foraita R, and Börnhorst C

Subjects
Blood Pressure Determination, Child, Child, Preschool, Chromatography, Gas, Cohort Studies, Cross-Sectional Studies, Delta-5 Fatty Acid Desaturase, Europe, Female, Genotyping Techniques, Heterozygote, Humans, Male, Models, Theoretical, Blood Pressure genetics, Body Mass Index, Fatty Acid Desaturases genetics, Fatty Acids blood, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
Abstract

Background: The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP., Methods: A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to <10 years from six European countries was included. The association between rs174546 (T

Published
2017
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14. Does the sex of one's co-twin affect height and BMI in adulthood? A study of dizygotic adult twins from 31 cohorts.

Author

Bogl LH, Jelenkovic A, Vuoksimaa E, Ahrenfeldt L, Pietiläinen KH, Stazi MA, Fagnani C, D'Ippolito C, Hur YM, Jeong HU, Silberg JL, Eaves LJ, Maes HH, Bayasgalan G, Narandalai D, Cutler TL, Kandler C, Jang KL, Christensen K, Skytthe A, Kyvik KO, Cozen W, Hwang AE, Mack TM, Derom CA, Vlietinck RF, Nelson TL, Whitfield KE, Corley RP, Huibregtse BM, McAdams TA, Eley TC, Gregory AM, Krueger RF, McGue M, Pahlen S, Willemsen G, Bartels M, van Beijsterveldt TCEM, Pang Z, Tan Q, Zhang D, Martin NG, Medland SE, Montgomery GW, Hjelmborg JVB, Rebato E, Swan GE, Krasnow R, Busjahn A, Lichtenstein P, Öncel SY, Aliev F, Baker LA, Tuvblad C, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Magnusson PKE, Pedersen NL, Aslan AKD, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Duncan GE, Buchwald D, Tarnoki AD, Tarnoki DL, Yokoyama Y, Hopper JL, Loos RJF, Boomsma DI, Sørensen TIA, Silventoinen K, and Kaprio J

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Body Height, Body Mass Index, Twins, Dizygotic
Abstract

Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs., Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese., Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance., Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

Published
2017
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15. Prevalence and correlates of binge eating disorder related features in the community.

Author

Mustelin L, Bulik CM, Kaprio J, and Keski-Rahkonen A

Subjects
Adult, Binge-Eating Disorder psychology, Cluster Analysis, Cross-Sectional Studies, Female, Finland epidemiology, Humans, Longitudinal Studies, Male, Middle Aged, Prevalence, Prospective Studies, Stress, Psychological psychology, Surveys and Questionnaires, Binge-Eating Disorder epidemiology, Body Mass Index, Feeding Behavior psychology, Stress, Psychological epidemiology
Abstract

Binge eating disorder (BED) is associated with high levels of obesity and psychological suffering, but little is known about 1) the distribution of features of BED in the general population and 2) their consequences for weight development and psychological distress in young adulthood. We investigated the prevalence of features of BED and their association with body mass index (BMI) and psychological distress among men (n = 2423) and women (n = 2825) from the longitudinal community-based FinnTwin16 cohort (born 1975-1979). Seven eating-related cognitions and behaviors similar to the defining features of BED were extracted from the Eating Disorder Inventory-2 and were assessed at a mean age of 24. BMI and psychological distress, measured with the General Health Questionnaire, were assessed at ages 24 and 34. We assessed prevalence of the features and their association with BMI and psychological distress cross-sectionally and prospectively. More than half of our participants reported at least one feature of BED; clustering of several features in one individual was less common, particularly among men. The most frequently reported feature was 'stuffing oneself with food', whereas the least common was 'eating or drinking in secrecy'. All individual features of BED and their clustering particularly were associated with higher BMI and more psychological distress cross-sectionally. Prospectively, the clustering of features of BED predicted increase in psychological distress but not additional weight gain when baseline BMI was accounted for. In summary, although some features of BED were common, the clustering of several features in one individual was not. The features were cumulatively associated with BMI and psychological distress and predicted further increase in psychological distress over ten years of follow-up., (Copyright © 2016. Published by Elsevier Ltd.)

Published
2017
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16. Leisure-time physical inactivity and association with body mass index: a Finnish Twin Study with a 35-year follow-up.

Author

Piirtola M, Kaprio J, Waller K, Heikkilä K, Koskenvuo M, Svedberg P, Silventoinen K, Kujala UM, and Ropponen A

Subjects
Adult, Aged, Female, Finland, Follow-Up Studies, Health Behavior, Humans, Linear Models, Male, Middle Aged, Surveys and Questionnaires, Young Adult, Body Mass Index, Exercise, Leisure Activities, Sedentary Behavior, Weight Gain
Abstract

Background: We investigated the stability and change of leisure-time physical inactivity in adult men and women during a 35-year follow-up. We also analysed the impact of long-term physical inactivity on the development of body mass index (BMI)., Methods: : In this population-based cohort study, 5254 Finnish twin individuals (59% women) participated in four surveys in 1975, 1981, 1990 and 2011. Mean age at baseline was 23.9 years. Individual long-term leisure-time physical activity (LTPA) was categorized into seven classes varying from 'persistently inactive' to 'persistently active'. We used the multivariate multilevel mixed-effects linear regression model and paired-sample t-test in the analyses. Co-twin control design was used for examining within-pair associations., Results: : Of men 11%, and of women 8%, were persistently inactive. Among both sexes, the mean BMI slope trajectories were steeper among the persistently inactive and those who became inactive than among those who were persistently active. Overall, the inactive participants gained 1.4 kg/m 2 [95% confidence interval (CI) 1.2 to 1.7] more in weight than did the active participants from 1975 to 2011. Among twin pairs discordant for LTPA, the corresponding difference was 1.4 kg/m 2 (95% CI 0.83 to 2.0) in dizygotic pairs and 0.68 kg/m 2 (95% CI 0.05 to1.3) in monozygotic pairs., Conclusions: Over a 35-year time span from young adulthood, persistently inactive participants and those who had become inactive had greater weight increases than those who were persistently active. This association was also found in twin-pair analyses, although attenuated in monozygotic pairs. This may support the importance of LTPA in weight management, although further causal inference is required., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Published
2017
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17. Body Mass Index and Depressive Symptoms: Testing for Adverse and Protective Associations in Two Twin Cohort Studies.

Author

Jokela M, Berg V, Silventoinen K, Batty GD, Singh-Manoux A, Kaprio J, Davey Smith G, and Kivimäki M

Subjects
Adult, Cohort Studies, Depressive Disorder genetics, Diseases in Twins, Female, Finland, Humans, Male, Middle Aged, Models, Genetic, Twins, Dizygotic genetics, Twins, Monozygotic genetics, United States, Body Mass Index, Depressive Disorder physiopathology
Abstract

Studies have suggested both adverse and protective associations of obesity with depressive symptoms. We examined the contribution of environmental and heritable factors in this association. Participants were same-sex twin pairs from two population-based twin cohort studies, the Older Finnish Twin Cohort (n = 8,215; mean age = 44.1) and the US Midlife Development in the United States (MIDUS; n = 1,105; mean age = 45.1). Body mass index (BMI) was calculated from self-reported height and weight. Depressive symptoms were assessed using Beck's Depression Inventory (BDI; Finnish Twin Cohort), and by negative and positive affect scales (MIDUS). In the Finnish Twin Cohort, higher BMI was associated with higher depressive symptoms in monozygotic (MZ) twins (B = 2.01, 95% CI = 1.0, 3.0) and dizygotic (DZ) twins (B = 1.17, 0.5, 1.9) with BMI >22. This association was observed in within-pair analysis in DZ twins (B = 1.47, CI = 0.4, 2.6) but not in within-pair analysis of MZ twins (B = 0.03, CI = -1.9, 2.0). Consistent with the latter result, a bivariate genetic model indicated that the association between higher BMI and higher depressive symptoms was largely mediated by genetic factors. The results of twin-pair analysis and bivariate genetic model were replicated in the MIDUS sample. These findings suggest an association between obesity and higher depressive symptoms, which is largely explained by shared heritable biological mechanisms.

Published
2016
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18. Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study.

Author

Silventoinen K, Jelenkovic A, Sund R, Hur YM, Yokoyama Y, Honda C, Hjelmborg Jv, Möller S, Ooki S, Aaltonen S, Ji F, Ning F, Pang Z, Rebato E, Busjahn A, Kandler C, Saudino KJ, Jang KL, Cozen W, Hwang AE, Mack TM, Gao W, Yu C, Li L, Corley RP, Huibregtse BM, Christensen K, Skytthe A, Kyvik KO, Derom CA, Vlietinck RF, Loos RJ, Heikkilä K, Wardle J, Llewellyn CH, Fisher A, McAdams TA, Eley TC, Gregory AM, He M, Ding X, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Tarnoki AD, Tarnoki DL, Stazi MA, Fagnani C, D'Ippolito C, Knafo-Noam A, Mankuta D, Abramson L, Burt SA, Klump KL, Silberg JL, Eaves LJ, Maes HH, Krueger RF, McGue M, Pahlen S, Gatz M, Butler DA, Bartels M, van Beijsterveldt TC, Craig JM, Saffery R, Freitas DL, Maia JA, Dubois L, Boivin M, Brendgen M, Dionne G, Vitaro F, Martin NG, Medland SE, Montgomery GW, Chong Y, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Tynelius P, Lichtenstein P, Haworth CM, Plomin R, Bayasgalan G, Narandalai D, Harden KP, Tucker-Drob EM, Öncel SY, Aliev F, Spector T, Mangino M, Lachance G, Baker LA, Tuvblad C, Duncan GE, Buchwald D, Willemsen G, Rasmussen F, Goldberg JH, Sørensen TIa, Boomsma DI, and Kaprio J

Subjects
Adolescent, Adult, Age Factors, Australia, Child, Child, Preschool, Europe, Asia, Eastern, Female, Humans, Infant, Male, North America, Obesity ethnology, Obesity genetics, Sex Factors, Young Adult, Body Mass Index, Environment, Gene-Environment Interaction, Genetic Variation, Obesity etiology, Twins, Dizygotic genetics, Twins, Monozygotic genetics
Abstract

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking., Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments., Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling., Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions., Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity., (© 2016 American Society for Nutrition.)

Published
2016
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19. Stability and change of body mass index as a predictor of disability pension.

Author

Ropponen A, Silventoinen K, Koskenvuo M, Svedberg P, and Kaprio J

Subjects
Adult, Cohort Studies, Female, Finland, Humans, Male, Middle Aged, Musculoskeletal Diseases genetics, Risk, Body Mass Index, Disabled Persons statistics & numerical data, Musculoskeletal Diseases diagnosis, Pensions statistics & numerical data
Abstract

Aims: To investigate whether stability or change in body mass index (BMI) predict disability pension (DP) due to musculoskeletal diagnosis (MSD) when controlling for familial confounding., Methods: Our study cohort consisted of 17,169 Finnish twins born before 1958. Data on BMI and multiple covariates from questionnaires in 1975 and 1981 were included and DPs were collected from the national pension registers until the end of 2004. Cox proportional hazards regression models with Hazard Ratios (HR) and 95% Confidence Intervals (CI) were used for statistical analyses., Results: General DP was granted to 2853 individuals and DP due to MSD to 1143 individuals during the 23-year follow-up. A one-unit increase in BMI in both 1975 (HR 1.08, 95% CI 1.05, 1.10) and 1981 (HR 1.06, 95% CI 1.04, 1.07), as well as the stability of and change in BMI from 1975 to 1981 were all associated with an increased risk of DP. These associations held in the analyses controlling for multiple covariates (age, sex, socioeconomic status, education, marital status, leisure-time physical activity, and musculoskeletal pain), and mainly also familial confounding, that is, genetics and shared environment. HR for stable obesity was 2.28 (95% CI 1.69, 3.08) for DP due to MSD, and 1.91 (95% CI 1.56, 2.34) for general DP in the fully adjusted models. CONCLUSIONS BMI IS AN EARLY PREDICTOR OF GENERAL DP AND ALSO OF DP DUE TO MSD OWING TO THE INDEPENDENCY OF VARIOUS COVARIATES AND POTENTIALLY ALSO FAMILIAL CONFOUNDING, BMI MAY POSSIBLY HAVE A DIRECT EFFECT ON THE RISK OF DP., (© 2016 the Nordic Societies of Public Health.)

Published
2016
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20. Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project.

Author

Yokoyama Y, Jelenkovic A, Sund R, Sung J, Hopper JL, Ooki S, Heikkilä K, Aaltonen S, Tarnoki AD, Tarnoki DL, Willemsen G, Bartels M, van Beijsterveldt TC, Saudino KJ, Cutler TL, Nelson TL, Whitfield KE, Wardle J, Llewellyn CH, Fisher A, He M, Ding X, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Song YM, Yang S, Lee K, Jeong HU, Knafo-Noam A, Mankuta D, Abramson L, Burt SA, Klump KL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Harris JR, Brandt I, Nilsen TS, Craig JM, Saffery R, Ji F, Ning F, Pang Z, Dubois L, Boivin M, Brendgen M, Dionne G, Vitaro F, Martin NG, Medland SE, Montgomery GW, Magnusson PK, Pedersen NL, Aslan AK, Tynelius P, Haworth CM, Plomin R, Rebato E, Rose RJ, Goldberg JH, Rasmussen F, Hur YM, Sørensen TI, Boomsma DI, Kaprio J, and Silventoinen K

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Pregnancy, Twins, Dizygotic, Twins, Monozygotic, Birth Order, Body Height genetics, Body Mass Index, Pregnancy, Twin genetics
Abstract

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Published
2016
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21. Ideals versus reality: Are weight ideals associated with weight change in the population?

Author

Kärkkäinen U, Mustelin L, Raevuori A, Kaprio J, and Keski-Rahkonen A

Subjects
Adult, Female, Finland, Humans, Longitudinal Studies, Male, Prospective Studies, Young Adult, Body Mass Index, Body Weights and Measures psychology, Ideal Body Weight, Weight Gain
Abstract

Objective: To quantify weight ideals of young adults and to examine whether the discrepancy between actual and ideal weight is associated with 10-year body mass index (BMI) change in the population., Methods: This study comprised 4,964 adults from the prospective population-based FinnTwin16 study. They reported their actual and ideal body weight at age 24 (range 22-27) and 10 years later (attrition 24.6%). The correlates of discrepancy between actual and ideal body weight and the impact on subsequent BMI change were examined., Results: The discrepancy between actual and ideal weight at 24 years was on average 3.9 kg (1.4 kg/m(2) ) among women and 1.2 kg (0.4 kg/m(2) ) among men. On average, participants gained weight during follow-up irrespective of baseline ideal weight: women ¯x = +4.8 kg (1.7 kg/m(2) , 95% CI 1.6-1.9 kg/m(2) ), men ¯x = +6.3 kg (2.0 kg/m(2) , 95% CI 1.8-2.1 kg/m(2) ). Weight ideals at 24 years were not correlated with 10-year weight change. At 34 years, just 13.2% of women and 18.9% of men were at or below the weight they had specified as their ideal weight at 24 years. Women and men adjusted their ideal weight upward over time., Conclusions: Irrespective of ideal weight at baseline, weight gain was nearly universal. Weight ideals were shifted upward over time., (© 2016 The Obesity Society.)

Published
2016
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22. Dietary Intake at 9 Years and Subsequent Body Mass Index in Adolescent Boys and Girls: A Study of Monozygotic Twin Pairs.

Author

Dubois L, Diasparra M, Bogl LH, Fontaine-Bisson B, Bédard B, Tremblay RE, Kaprio J, and Boivin M

Subjects
Adolescent, Child, Dietary Carbohydrates administration & dosage, Dietary Carbohydrates analysis, Dietary Fats administration & dosage, Dietary Fats analysis, Dietary Proteins administration & dosage, Dietary Proteins analysis, Female, Fruit, Humans, Male, Mental Recall, Obesity prevention & control, Prospective Studies, Quebec, Sex Factors, Socioeconomic Factors, Vegetables, Weight Gain, Whole Grains, Body Mass Index, Energy Intake, Feeding Behavior, Twins, Monozygotic
Abstract

There is a lack of evidence pointing to specific dietary elements related to weight gain and obesity prevention in childhood and adulthood. Dietary intake and obesity are both inherited and culturally transmitted, but most prospective studies on the association between diet and weight status do not take genetics into consideration. The objective of this study was to document the association between dietary intake at 9 years and subsequent Body Mass Index (BMI) in adolescent monozygotic boy and girl twin pairs. This research used data from 152 twin pairs. Dietary data were collected from two 24-hour-recall interviews with a parent and the child aged 9 years. Height and weight were obtained when the twins were aged 9, 12, 13, and 14 years. Intrapair variability analysis was performed to identify dietary elements related to BMI changes in subsequent years. BMI-discordant monozygotic twin pairs were also identified to analyze the dietary constituents that may have generated the discordance. After eliminating potential confounding genetic factors, pre-adolescent boys who ate fewer grain products and fruit and consumed more high-fat meat and milk had higher BMIs during adolescence; pre-adolescent girls who consumed more grain products and high-fat meat and milk had higher BMIs during adolescence. Energy intake (EI) at 9 years was not related to BMI in subsequent years. Our study suggests that messages and interventions directed at obesity prevention could take advantage of sex-specific designs and' eventually' genetic information.

Published
2016
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23. Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass.

Author

Bahl A, Pöllänen E, Ismail K, Sipilä S, Mikkola TM, Berglund E, Lindqvist CM, Syvänen AC, Rantanen T, Kaprio J, Kovanen V, and Ollikainen M

Subjects
Female, Genome-Wide Association Study, Humans, Adiposity genetics, Body Mass Index, Bone Density, DNA Methylation, Gene Expression, Hormone Replacement Therapy, Leukocytes, Postmenopause genetics
Abstract

The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.

Published
2015
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24. Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project.

Author

Jelenkovic A, Yokoyama Y, Sund R, Honda C, Bogl LH, Aaltonen S, Ji F, Ning F, Pang Z, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Burt SA, Klump KL, Medland SE, Montgomery GW, Kandler C, McAdams TA, Eley TC, Gregory AM, Saudino KJ, Dubois L, Boivin M, Tarnoki AD, Tarnoki DL, Haworth CM, Plomin R, Öncel SY, Aliev F, Stazi MA, Fagnani C, D'Ippolito C, Craig JM, Saffery R, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Spector T, Mangino M, Lachance G, Gatz M, Butler DA, Bayasgalan G, Narandalai D, Freitas DL, Maia JA, Harden KP, Tucker-Drob EM, Kim B, Chong Y, Hong C, Shin HJ, Christensen K, Skytthe A, Kyvik KO, Derom CA, Vlietinck RF, Loos RJ, Cozen W, Hwang AE, Mack TM, He M, Ding X, Chang B, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, Aujard K, Magnusson PK, Pedersen NL, Aslan AK, Song YM, Yang S, Lee K, Baker LA, Tuvblad C, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Heikkilä K, Tan Q, Zhang D, Swan GE, Krasnow R, Jang KL, Knafo-Noam A, Mankuta D, Abramson L, Lichtenstein P, Krueger RF, McGue M, Pahlen S, Tynelius P, Duncan GE, Buchwald D, Corley RP, Huibregtse BM, Nelson TL, Whitfield KE, Franz CE, Kremen WS, Lyons MJ, Ooki S, Brandt I, Nilsen TS, Inui F, Watanabe M, Bartels M, van Beijsterveldt TC, Wardle J, Llewellyn CH, Fisher A, Rebato E, Martin NG, Iwatani Y, Hayakawa K, Sung J, Harris JR, Willemsen G, Busjahn A, Goldberg JH, Rasmussen F, Hur YM, Boomsma DI, Sørensen TI, Kaprio J, and Silventoinen K

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Cohort Studies, Databases, Factual, Female, Humans, Infant, Linear Models, Male, Middle Aged, Twins, Monozygotic, Young Adult, Body Height, Body Mass Index, Twins, Dizygotic
Abstract

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.

Published
2015
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25. The CODATwins Project: The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits.

Author

Silventoinen K, Jelenkovic A, Sund R, Honda C, Aaltonen S, Yokoyama Y, Tarnoki AD, Tarnoki DL, Ning F, Ji F, Pang Z, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Burt SA, Klump KL, Medland SE, Montgomery GW, Kandler C, McAdams TA, Eley TC, Gregory AM, Saudino KJ, Dubois L, Boivin M, Haworth CM, Plomin R, Öncel SY, Aliev F, Stazi MA, Fagnani C, D'Ippolito C, Craig JM, Saffery R, Siribaddana SH, Hotopf M, Sumathipala A, Spector T, Mangino M, Lachance G, Gatz M, Butler DA, Bayasgalan G, Narandalai D, Freitas DL, Maia JA, Harden KP, Tucker-Drob EM, Christensen K, Skytthe A, Kyvik KO, Hong C, Chong Y, Derom CA, Vlietinck RF, Loos RJ, Cozen W, Hwang AE, Mack TM, He M, Ding X, Chang B, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, Aujard K, Magnusson PK, Pedersen NL, Aslan AK, Song YM, Yang S, Lee K, Baker LA, Tuvblad C, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Heikkilä K, Tan Q, Zhang D, Swan GE, Krasnow R, Jang KL, Knafo-Noam A, Mankuta D, Abramson L, Lichtenstein P, Krueger RF, McGue M, Pahlen S, Tynelius P, Duncan GE, Buchwald D, Corley RP, Huibregtse BM, Nelson TL, Whitfield KE, Franz CE, Kremen WS, Lyons MJ, Ooki S, Brandt I, Nilsen TS, Inui F, Watanabe M, Bartels M, van Beijsterveldt TC, Wardle J, Llewellyn CH, Fisher A, Rebato E, Martin NG, Iwatani Y, Hayakawa K, Rasmussen F, Sung J, Harris JR, Willemsen G, Busjahn A, Goldberg JH, Boomsma DI, Hur YM, Sørensen TI, and Kaprio J

Subjects
Female, Humans, Male, Phenotype, Twin Studies as Topic, Anthropometry, Body Height genetics, Body Mass Index, Body Weight genetics, Gene-Environment Interaction, Twins genetics
Abstract

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

Published
2015
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26. Genetic studies of body mass index yield new insights for obesity biology.

Author

Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan J, Mägi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Zhao JH, Zhao W, Chen J, Fehrmann R, Hedman ÅK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham JL, Buyske S, Demirkan A, Deng G, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Goel A, Gong J, Jackson AU, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Leach IM, Medina-Gomez C, Medland SE, Nalls MA, Palmer CD, Pasko D, Pechlivanis S, Peters MJ, Prokopenko I, Shungin D, Stančáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Isaacs A, Albrecht E, Ärnlöv J, Arscott GM, Attwood AP, Bandinelli S, Barrett A, Bas IN, Bellis C, Bennett AJ, Berne C, Blagieva R, Blüher M, Böhringer S, Bonnycastle LL, Böttcher Y, Boyd HA, Bruinenberg M, Caspersen IH, Chen YI, Clarke R, Daw EW, de Craen AJM, Delgado G, Dimitriou M, Doney ASF, Eklund N, Estrada K, Eury E, Folkersen L, Fraser RM, Garcia ME, Geller F, Giedraitis V, Gigante B, Go AS, Golay A, Goodall AH, Gordon SD, Gorski M, Grabe HJ, Grallert H, Grammer TB, Gräßler J, Grönberg H, Groves CJ, Gusto G, Haessler J, Hall P, Haller T, Hallmans G, Hartman CA, Hassinen M, Hayward C, Heard-Costa NL, Helmer Q, Hengstenberg C, Holmen O, Hottenga JJ, James AL, Jeff JM, Johansson Å, Jolley J, Juliusdottir T, Kinnunen L, Koenig W, Koskenvuo M, Kratzer W, Laitinen J, Lamina C, Leander K, Lee NR, Lichtner P, Lind L, Lindström J, Lo KS, Lobbens S, Lorbeer R, Lu Y, Mach F, Magnusson PKE, Mahajan A, McArdle WL, McLachlan S, Menni C, Merger S, Mihailov E, Milani L, Moayyeri A, Monda KL, Morken MA, Mulas A, Müller G, Müller-Nurasyid M, Musk AW, Nagaraja R, Nöthen MM, Nolte IM, Pilz S, Rayner NW, Renstrom F, Rettig R, Ried JS, Ripke S, Robertson NR, Rose LM, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Scott WR, Seufferlein T, Shi J, Smith AV, Smolonska J, Stanton AV, Steinthorsdottir V, Stirrups K, Stringham HM, Sundström J, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Tayo BO, Thorand B, Thorleifsson G, Tyrer JP, Uh HW, Vandenput L, Verhulst FC, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Warren HR, Waterworth D, Weedon MN, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Brennan EP, Choi M, Dastani Z, Drong AW, Eriksson P, Franco-Cereceda A, Gådin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang J, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma B, McCarroll SA, McKnight AJ, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Okada Y, Perry JRB, Dorajoo R, Reinmaa E, Salem RM, Sandholm N, Scott RA, Stolk L, Takahashi A, Tanaka T, van 't Hooft FM, Vinkhuyzen AAE, Westra HJ, Zheng W, Zondervan KT, Heath AC, Arveiler D, Bakker SJL, Beilby J, Bergman RN, Blangero J, Bovet P, Campbell H, Caulfield MJ, Cesana G, Chakravarti A, Chasman DI, Chines PS, Collins FS, Crawford DC, Cupples LA, Cusi D, Danesh J, de Faire U, den Ruijter HM, Dominiczak AF, Erbel R, Erdmann J, Eriksson JG, Farrall M, Felix SB, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gejman PV, Gieger C, Gottesman O, Gudnason V, Gyllensten U, Hall AS, Harris TB, Hattersley AT, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Homuth G, Hovingh GK, Humphries SE, Hunt SC, Hyppönen E, Illig T, Jacobs KB, Jarvelin MR, Jöckel KH, Johansen B, Jousilahti P, Jukema JW, Jula AM, Kaprio J, Kastelein JJP, Keinanen-Kiukaanniemi SM, Kiemeney LA, Knekt P, Kooner JS, Kooperberg C, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Marchand LL, Lehtimäki T, Lyssenko V, Männistö S, Marette A, Matise TC, McKenzie CA, McKnight B, Moll FL, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Madden PAF, Pasterkamp G, Peden JF, Peters A, Postma DS, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Rioux JD, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schunkert H, Schwarz PEH, Sever P, Shuldiner AR, Sinisalo J, Stolk RP, Strauch K, Tönjes A, Trégouët DA, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Völker U, Waeber G, Willemsen G, Witteman JC, Zillikens MC, Adair LS, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bornstein SR, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PIW, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hui J, Hunter DJ, Hveem K, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Metspalu A, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CNA, Pedersen NL, Perola M, Pérusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sattar N, Schadt EE, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Thorsteinsdottir U, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Weir DR, Wichmann HE, Wilson JF, Zanen P, Borecki IB, Deloukas P, Fox CS, Heid IM, O'Connell JR, Strachan DP, Stefansson K, van Duijn CM, Abecasis GR, Franke L, Frayling TM, McCarthy MI, Visscher PM, Scherag A, Willer CJ, Boehnke M, Mohlke KL, Lindgren CM, Beckmann JS, Barroso I, North KE, Ingelsson E, Hirschhorn JN, Loos RJF, and Speliotes EK

Subjects
Adipogenesis genetics, Adiposity genetics, Age Factors, Energy Metabolism genetics, Europe ethnology, Female, Genetic Predisposition to Disease genetics, Glutamic Acid metabolism, Humans, Insulin metabolism, Insulin Secretion, Male, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Racial Groups genetics, Synapses metabolism, Body Mass Index, Genome-Wide Association Study, Obesity genetics, Obesity metabolism
Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015
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27. Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

Author

Taylor AE, Morris RW, Fluharty ME, Bjorngaard JH, Åsvold BO, Gabrielsen ME, Campbell A, Marioni R, Kumari M, Hällfors J, Männistö S, Marques-Vidal P, Kaakinen M, Cavadino A, Postmus I, Husemoen LL, Skaaby T, Ahluwalia TS, Treur JL, Willemsen G, Dale C, Wannamethee SG, Lahti J, Palotie A, Räikkönen K, Kisialiou A, McConnachie A, Padmanabhan S, Wong A, Dalgård C, Paternoster L, Ben-Shlomo Y, Tyrrell J, Horwood J, Fergusson DM, Kennedy MA, Frayling T, Nohr EA, Christiansen L, Ohm Kyvik K, Kuh D, Watt G, Eriksson J, Whincup PH, Vink JM, Boomsma DI, Davey Smith G, Lawlor D, Linneberg A, Ford I, Jukema JW, Power C, Hyppönen E, Jarvelin MR, Preisig M, Borodulin K, Kaprio J, Kivimaki M, Smith BH, Hayward C, Romundstad PR, Sørensen TI, Munafò MR, and Sattar N

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Genome-Wide Association Study, Genotype, Health Status, Humans, Middle Aged, Multigene Family, Polymorphism, Single Nucleotide, Severity of Illness Index, Smoking epidemiology, Weight Loss genetics, Young Adult, Body Mass Index, Nerve Tissue Proteins genetics, Receptors, Nicotinic genetics, Smoking genetics
Abstract

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Published
2014
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29. Longitudinal leisure-time physical activity profiles throughout adulthood and related characteristics: a 36-year follow-up study of the older Finnish Twin Cohort.

Author

Berntzen, Bram J., Tolvanen, Asko, Kujala, Urho M., Silventoinen, Karri, Vuoksimaa, Eero, Kaprio, Jaakko, and Aaltonen, Sari

Subjects
MENTAL depression risk factors, RISK assessment, RESEARCH funding, BODY mass index, EXERCISE, SPORTS, SEX distribution, SMOKING, SEDENTARY lifestyles, DESCRIPTIVE statistics, STRUCTURAL equation modeling, LEISURE, LONGITUDINAL method, SURVEYS, HEALTH behavior, TYPE 2 diabetes, BLOOD pressure, COMPARATIVE studies, PUBLIC health, PHYSICAL activity, TIME, MID-life crisis, EDUCATIONAL attainment, DISEASE risk factors, ADULTS
Abstract

Background: Personalized interventions aiming to increase physical activity in individuals are effective. However, from a public health perspective, it would be important to stimulate physical activity in larger groups of people who share the vulnerability to be physically inactive throughout adulthood. To find these high-risk groups, we identified 36-year leisure-time physical activity profiles from young adulthood to late midlife in females and males. Moreover, we uncovered which anthropometric-, demographic-, lifestyle-, and health-related characteristics were associated with these physical activity profiles. Methods: We included 2,778 females and 1,938 males from the population-based older Finnish Twin Cohort Study, who responded to health and behavior surveys at the mean ages of 24, 30, 40 and 60. Latent profile analysis was used to identify longitudinal leisure-time physical activity profiles. Results: We found five longitudinal leisure-time physical activity profiles for both females and males. Females' profiles were: 1) Low increasing moderate (29%), 2) Moderate stable (23%), 3) Very low increasing low (20%), 4) Low stable (20%) and 5) High increasing high (9%). Males' profiles were: 1) Low increasing moderate (29%), 2) Low stable very low (26%), 3) Moderate decreasing low (21%), 4) High fluctuating high (17%) and 5) Very low stable (8%). In both females and males, lower leisure-time physical activity profiles were associated with lower education, higher body mass index, smoking, poorer perceived health, higher sedentary time, high blood pressure, and a higher risk for type 2 diabetes. Furthermore, lower leisure-time physical activity was linked to a higher risk of depression in females. Conclusions: We found several longitudinal leisure-time physical activity profiles with unique changes in both sexes. Fewer profiles in females than in males remained or became low physically active during the 36-year follow-up. We observed that lower education, higher body mass index, and more smoking already in young adulthood were associated with low leisure-time physical activity profiles. However, the fact that several longitudinal profiles demonstrated a change in their physical activity behavior over time implies the potential for public health interventions to improve leisure-time physical activity levels. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Mental, physical, and social well-being and quality of life in healthy young adult twin pairs discordant and concordant for body mass index.

Author

Kupila, Sakris K. E., Berntzen, Bram J., Muniandy, Maheswary, Ahola, Aila J., Kaprio, Jaakko, Rissanen, Aila, and Pietiläinen, Kirsi H.

Subjects
WELL-being, YOUNG adults, BODY mass index, QUALITY of life, PHYSICAL mobility, LIFE satisfaction, SOCIAL anxiety
Abstract

Objective: The relationship between obesity and mental health is complex and is moderated by the level of obesity, age, sex, and social and genetic factors. In the current study, we used a unique co-twin control design, with twin pairs discordant for body mass index (BMI), to control for shared genetic and environmental effects between obesity and several dimensions of mental health. Methods: We studied 74 monozygotic (MZ) twin pairs, of whom 36 were BMI-discordant (intra-pair difference in BMI ≥ 3 kg/m2), and 77 dizygotic (DZ) twin pairs (46 BMI-discordant). We assessed subjective health, especially mental health and mental well-being (depression, anxiety, self-esteem, health-related quality of life, life satisfaction, and social well-being) through questionnaires. Results: Heavier MZ co-twins from BMI-discordant pairs had poorer general health (58.8±3.0 vs. 72.4±3.8, P = 0.001, FDR = 0.017 on a scale from 0 to 100 where higher scores indicate more positive results), physical functioning (90.3±1.1 vs. 95.5±2.2, P = 0.024, FDR = 0.122), energy levels (55.6±3.4 vs. 66.6±3.3, P = 0.013, FDR = 0.109), and emotional well-being (65.9±3.2 vs. 75.4±2.9, P = 0.031, FDR = 0.122), as well as a tendency for depressive symptoms (8.4±1.3 vs. 5.6±0.9, P = 0.071, FDR = 0.166) compared to their leaner co-twins. Heavier DZ co-twins had poorer total physical well-being (91.6±1.9 vs. 95.6±1.0, P = 0.035, FDR = 0.356) and more depressive symptoms (4.3±0.9 vs. 2.4±0.5, P = 0.016, FDR = 0.345 on a scale from 0 to 63 where lower scores indicate fewer depressive symptoms) than their leaner co-twins. Association analyses, using all twin pairs, confirmed that higher BMI within pairs linked to general health, physical functioning and depressive symptoms. No association was found between BMI and anxiety, self-esteem, life satisfaction, or social well-being. Conclusions: In conclusion, this study underscores the notable association between elevated BMI and physical well-being and to a lesser extent between elevated BMI and depressive symptoms, while revealing no discernible connections with anxiety, self-esteem, life satisfaction, or social well-being. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Mortality Associations With DNA Methylation-Based Biological Aging and Physical Functioning Measures Across a 20-Year Follow-up Period.

Author

Föhr, Tiina, Waller, Katja, Viljanen, Anne, Rantanen, Taina, Kaprio, Jaakko, Ollikainen, Miina, and Sillanpää, Elina

Subjects
PHYSICAL mobility, AGE, BODY mass index, DNA methylation, AGING
Abstract

Background Measures of biological aging range from DNA methylation (DNAm)-based estimates to measures of physical abilities. The purpose of this study was to compare DNAm- and physical functioning-based measures of biological aging in predicting mortality. Methods We studied 63- to 76-year-old women (N = 395) from the Finnish Twin Study on Aging (FITSA). Participants' biological age (epigenetic clocks DNAm GrimAge and DunedinPACE) was estimated using blood DNAm data. Tests of physical functioning conducted under standardized laboratory conditions included the Timed Up and Go (TUG) test and 10-m walk test. Mortality hazard ratios were calculated per every 1 standard deviation (SD) increase in the predictor. Cox regression models were conducted for individuals and twin pairs, the latter controlling for underlying genetic effects. The models were adjusted for known lifestyle predictors of mortality. Results During the follow-up period (mean 17.0 years, range 0.2–20.3), 187 participants died. In both the individual-based and pairwise analyses, GrimAge and both functional biomarkers of aging were associated with mortality independent of family relatedness, chronological age, physical activity, body mass index, smoking, education, or chronic diseases. In a model including both the DNAm-based measures and functional biomarkers of aging, GrimAge and TUG remained predictive. Conclusions The findings suggest that DNAm GrimAge and the TUG test are strong predictors of mortality independent of each others and genetic influences. DNAm-based measures and functional tests capture different aspects of the aging process and thus complement each other as measures of biological aging in predicting mortality. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes.

Author

Garske, Kristina M., Kar, Asha, Comenho, Caroline, Balliu, Brunilda, Pan, David Z., Bhagat, Yash V., Rosenberg, Gregory, Koka, Amogha, Das, Sankha Subhra, Miao, Zong, Sinsheimer, Janet S., Kaprio, Jaakko, Pietiläinen, Kirsi H., and Pajukanta, Päivi

Subjects
HUMAN chromatin, BODY mass index, TWINS, GENOTYPE-environment interaction, INFLAMMATION, C-reactive protein, CHROMATIN
Abstract

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset (~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions. Preadipocytes contribute to the pro-inflammatory environment in obesity, via unknown mechanisms. Here, comparing monozygotic twin pairs, the authors show that co-accessibility of chromatin in preadipocytes is altered in siblings with higher compared to lower BMI, and that variants in these regions contribute to systemic inflammation via interactions with BMI. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Genetic and Environmental Factors Underlying Parallel Changes in Body Mass Index and Alcohol Consumption: A 36-Year Longitudinal Study of Adult Twins.

Author

Drouard, Gabin, Silventoinen, Karri, Latvala, Antti, and Kaprio, Jaakko

Subjects
COMPULSIVE eating, BODY mass index, SUNBURN, FETOFETAL transfusion, ALCOHOLISM, LONGITUDINAL method
Abstract

Although we found no genetic correlation between baseline BMI and alcohol consumption, a genetic correlation associating baseline BMI with a change in alcohol consumption was observed in both men and women. The aims of the current study were therefore (1) to study the relationship between BMI and alcohol consumption trajectories, (2) to highlight the genetic and environmental components underlying changes in BMI and alcohol consumption, and (3) to investigate possible genetic and environmental correlations between BMI and alcohol consumption trajectories. Obesity and heavy alcohol consumption are major public health issues worldwide due to their high and increasing prevalence in recent decades [[1]]. These results support the existence of complex genetic architectures influencing (1) alcohol consumption and changes in alcohol consumption, (2) BMI with changes in BMI, and (3) BMI intercept with alcohol-related behavior over time. [Extracted from the article]

Published
2023
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34. Family structure in relation to body mass index and metabolic score in European children and adolescents

Author

Stahlmann, Katharina, Lissner, Lauren, Bogl, Leonie H., Mehlig, Kirsten, Kaprio, Jaakko, Klosowska, Joanna, Moreno, Luis A., Veidebaum, Toomas, Solea, Antonia, Molnar, Denes, Lauria, Fabio, Boernhorst, Claudia, Wolters, Maike, Hebestreit, Antje, Hunsberger, Monica, Family Consortia, IDEFICS I, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, and Hjelt Institute (-2014)

Subjects
Parents, Adolescent, PARTICIPATION, Social Sciences, Body Mass Index, BMI, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, Humans, family structure, Obesity, RISK, Family Characteristics, Nutrition and Dietetics, OVERWEIGHT, Health Policy, Public Health, Environmental and Occupational Health, single parent, metabolic score, PREVENTION, Cross-Sectional Studies, Pediatrics, Perinatology and Child Health, only child, overweight, CHILDHOOD OBESITY, BEHAVIOR
Abstract

Background Living in single parent and blended families or as an only child-compared to living in two-parent biological families or with siblings, respectively-is associated with a higher body mass index (BMI) in cross-sectional studies. However, longitudinal research addressing the children's BMI in this context is scarce. Further, little is known about the association between family structure and metabolic health. Objectives This study aimed at investigating the association between both aspects of family structure with BMI and a metabolic score (MetS). Methods Cross-sectional data from 7804 children participating in the European multi-center I.Family study (2013/2014) and longitudinal data from 5621 children who also participated previously in the IDEFICS study (2007-2010) were used. Family structure was assessed by a detailed interview. BMI z-score and the MetS were based on measured anthropometry, blood pressure, high-density lipoprotein, blood glucose, and triglycerides. Linear regressions were performed to model associations between family structure with BMI and MetS. Results Children from single-parent families had higher BMI z-scores in the cross-sectional (beta = 0.09, 95% confidence interval [CI]: 0.001 to 0.18) and longitudinal analyses compared to those from two-parent families. Cross-sectionally, the number of siblings was associated with lower BMI z-scores (beta = -0.07, 95% CI: -0.10 to -0.03) and lower MetS (beta = -0.14, 95% CI: -0.26 to -0.01). Longitudinally, only children between baseline and follow-up had higher BMI z-scores at follow-up (beta = 0.07, 95% CI: 0.01 to 0.14) compared to stable siblings. Conclusion Obesity prevention measures should focus on single-parent households and families with an only child.

Published
2022

35. Associations of sleep duration and screen time with incidence of overweight in european children : the IDEFICS/I.Family cohort

Author

Guzman, Viveka, Lissner, Lauren, Arvidsson, Louise, Hebestreit, Antje, Solea, Antonia, Lauria, Fabio, Kaprio, Jaakko, Reisch, Lucia A., Moreno Aznar, Luis A., Felsõ, Regina, De Henauw, Stefaan, Veidebaum, Toomas, Ahrens, Wolfgang, Hunsberger, Monica, The IDEFICS Consortium, The I.Family Consortium, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Department of Public Health, and Genetic Epidemiology

Subjects
PRESCHOOL-CHILDREN, Pediatric Obesity, Health (social science), Psychological intervention, Overweight, Logistic regression, Body Mass Index, 0302 clinical medicine, ADOLESCENTS, Medicine and Health Sciences, TX341-641, 030212 general & internal medicine, Nutritional diseases. Deficiency diseases, Child, Children, 2. Zero hunger, Incidence, Incidence (epidemiology), 1184 Genetics, developmental biology, physiology, Public Health, Global Health, Social Medicine and Epidemiology, Sleep time, Cohort, CHILDHOOD OBESITY, 3143 Nutrition, medicine.symptom, Research Article, RC620-627, Health(social science), Screen Time, 03 medical and health sciences, Screen time, Obesity, Screen duration, Physiology (medical), medicine, Humans, Nutrition. Foods and food supply, business.industry, 030229 sport sciences, medicine.disease, TRENDS, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, RISK-FACTORS, 3111 Biomedicine, Sleep, business, Weight gain, Demography
Abstract

INTRODUCTION: Over the past decades, children have been increasingly using screen devices, while at the same time their sleep duration has decreased. Both behaviors have been associated with excess weight, and it is possible they act as mutually reinforcing behaviors for weight gain. The aim of the study was to explore independent, prospective associations of screen time and sleep duration with incident overweight in a sample of European children. METHODS: Data from 4,285 children of the IDEFICS/I.Family cohort who were followed up from 2009/2010 to 2013/2014 were analyzed. Hours per day of screen time and of sleep duration were reported by parents at baseline. Logistic regression analyses were carried out in separate and mutually adjusted models controlled for sex, age, European country region, parental level of education, and baseline BMI z-scores. RESULTS: Among normal weight children at baseline (N = 3,734), separate models suggest that every hour increase in screen time and every hour decrease in sleep duration were associated with higher odds of the child becoming overweight or obese at follow-up (OR = 1.16, 95% CI: 1.02-1.32 and OR = 1.23, 95% CI: 1.05-1.43, respectively). In the mutually adjusted model, both associations were attenuated slightly ( screen time OR = 1.13, 95% CI: 0.99-1.28; sleep duration OR = 1.20, 95% CI: 1.03-1.40), being consistently somewhat stronger for sleep duration. DISCUSSION/CONCLUSION: Both screen time and sleep duration increased the incidence of overweight or obesity by 13-20%. Interventions that include an emphasis on adequate sleep and minimal screen time are needed to establish their causal role in the prevention of overweight and obesity among European children. CC BY-NC 4.0https://www.karger.com/open-access/types-licences-copyright-costsPublished online: November 1, 2021Correspondence to: Monica Hunsberger, monica.hunsberger@gu.seFunding SourcesV.G.’s contribution to this study was supported by the Swedish Institute. The Swedish section of this study was co-financed by the Swedish Research Council for Environment, Agricultural Sciences, and Spatial Planning (2012-00038), the Swedish Research Council (2015-02508), the ALF-agreement for western Sweden (ALFGBG-722441), and the Swedish Research Council for Health, Working Life and Welfare (FORTE Grant 2014-01994).

Published
2022

36. The temporal relationship between parental concern of overeating and childhood obesity considering genetic susceptibility : longitudinal results from the IDEFICS/I.Family study

Author

IDEFICS and I.Family consortia, Masip-Manuel, Guiomar, Foraita, Ronja, Silventoinen, Karri, Keski-Rahkonen, Anna, Bogl, Leonie-Helen, Kaprio, Jaakko, Department of Public Health, Helsinki Inequality Initiative (INEQ), Demography, Population Research Unit (PRU), Center for Population, Health and Society, Sociology, Anna Keski-Rahkonen / Principal Investigator, and Institute for Molecular Medicine Finland

Subjects
OVERWEIGHT, EATING BEHAVIOR, Mediation, TWIN, PATHWAYS, 3142 Public health care science, environmental and occupational health, BODY-MASS INDEX, POOLED ANALYSIS, ENERGY-INTAKE, Overeating, Polygenic risk score, Temporal associations, 5141 Sociology, Genetics, Obesity, WEIGHT, Body mass index, EXPENDITURE, ASSOCIATIONS
Abstract

Background: Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. Methods: The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean +/- SD follow-up 5.8 +/- 0.4). Children examined in 2007/2008 (wave 1) (mean +/- SD age: 4.4 +/- 1.1, range: 2-9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. Results: In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (beta = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (beta = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (beta = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (beta = 0.09, 95% CI: 0.07, 0.12). Conclusions: The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain.

Published
2021

37. Parental education and genetics of body mass index from infancy to old age: a pooled analysis of 29 twin cohorts

Author

Silventoinen, Karri, Jelenkovic, Aline, Latvala, Antti, Yokoyama, Yoshie, Sund, Reijo, Sugawara, Masumi, Tanaka, Mami, Matsumoto, Satoko, Aaltonen, Sari, Piirtola, Maarit, Freitas, Duarte L, Maia, José A, Öncel, Sevgi Y, Aliev, Fazil, Ji, Fuling, Ning, Feng, Pang, Zengchang, Rebato, Esther, Saudino, Kimberly J, Cutler, Tessa L, Hopper, John L, Ullemar, Vilhelmina, Almqvist, Catarina, Magnusson, Patrik KE, Cozen, Wendy, Hwang, Amie E, Mack, Thomas M, Willemsen, Gonneke, Bartels, Meike, van Beijsterveldt, Catharina EM, Nelson, Tracy L, Whitfield, Keith E, Sung, Joohon, Kim, Jina, Lee, Jooyeon, Lee, Sooji, Llewellyn, Clare H, Fisher, Abigail, Medda, Emanuela, Nisticò, Lorenza, Toccaceli, Virgilia, Baker, Laura A, Tuvblad, Catherine, Corley, Robin P, Huibregtse, Brooke M, Derom, Catherine A, Vlietinck, Robert F, Loos, Ruth JF, Knafo-Noam, Ariel, Mankuta, David, Abramson, Lior, Burt, S Alexandra, Klump, Kelly L, Silberg, Judy L, Maes, Hermine H, Krueger, Robert F, McGue, Matt, Pahlen, Shandell, Gatz, Margaret, Butler, David A, Harris, Jennifer R, Nilsen, Thomas S, Harden, K Paige, Tucker-Drob, Elliot M, Franz, Carol E, Kremen, William S, Lyons, Michael J, Lichtenstein, Paul, Jeong, Hoe-Uk, Hur, Yoon-Mi, Boomsma, Dorret I, Sørensen, Thorkild IA, and Kaprio, Jaakko

Subjects
Adult, Male, Parents, Adolescent, parental education, Twins, nutritional and metabolic diseases, Infant, body mass index, Middle Aged, Article, Cohort Studies, Young Adult, Child, Preschool, Humans, genetics, Female, Gene-Environment Interaction, international comparisons, Child, Aged
Abstract

Objective: To analyze how parental education modifies the genetic and environmental variances of body mass index (BMI) from infancy to old age in three geographic-cultural regions. Methods: A pooled sample of 29 cohorts including 143 499 twin individuals with information on parental education and BMI from 1 to 79 years (299 201 BMI measures) was analyzed by genetic twin modeling. Results: Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low educational category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia. Conclusions: Lower parental education is associated with higher mean and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay between genetic predisposition, childhood social environment and macro-social context is important for socio-economic differences in BMI.

Published
2019

38. Molecular pathways behind acquired obesity : Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI

Author

van der Kolk, Birgitta W., Saari, Sina, Lovric, Alen, Arif, Muhammad, Alvarez, Marcus, Ko, Arthur, Miao, Zong, Sahebekhtiari, Navid, Muniandy, Maheswary, Heinonen, Sini, Oghabian, Ali, Jokinen, Riikka, Jukarainen, Sakari, Hakkarainen, Antti, Lundbom, Jesper, Kuula, Juho, Groop, Per-Henrik, Tukiainen, Taru, Lundbom, Nina, Rissanen, Aila, Kaprio, Jaakko, Williams, Evan Graehl, Zamboni, Nicola, Mardinoglu, Adil, Pajukanta, Päivi, Pietiläinen, Kirsi H., CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Diabetes and Obesity Research Program, Research Programs Unit, Institute for Molecular Medicine Finland, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, HUS Diagnostic Center, HUS Abdominal Center, Department of Medicine, Per Henrik Groop / Principal Investigator, Clinicum, Nefrologian yksikkö, Genomics of Sex Differences, Molecular and Integrative Biosciences Research Programme, Helsinki University Hospital Area, and HUS Internal Medicine and Rehabilitation

Subjects
Medicine (General), obesity, genome-scale metabolic models, Subcutaneous Fat, Biochemistry, biophysics & molecular biology [F05] [Life sciences], Article, Body Mass Index, adipose tissue, metabolomics, multiomics, proteomics, skeletal muscle, transcriptomics, twins, R5-920, INFLAMMATION, Adipocytes, TRANSCRIPTOME, Muscle, Skeletal, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], SIGNATURES, GENE-EXPRESSION, INSULIN-RESISTANCE, IDENTIFICATION, Twins, Monozygotic, Mitochondria, PROTEOME, ACID, 1182 Biochemistry, cell and molecular biology, ACCURATE, HEALTH, Insulin Resistance
Abstract

Summary Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity., Graphical abstract, Highlights Multiomics analyses of adipose tissue and skeletal muscle in BMI-discordant twins Excess body weight downregulates mitochondrial pathways in both tissues Excess body weight upregulates proinflammatory pathways in both tissues Adipose tissue alterations are associated with metabolic health in acquired obesity, In adipose tissue and skeletal muscle of BMI-discordant monozygotic twin pairs, van der Kolk et al. demonstrate that excess body weight is associated with downregulated mitochondrial pathways and upregulated proinflammatory pathways. Furthermore, adipose tissue metabolic alterations appear to be more pronounced than those in muscle, whereas only adipose tissue alterations are associated with metabolic health.

Published
2021

39. BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for body mass index.

Author

Lundgren, Sara, Kuitunen, Sara, Pietiläinen, Kirsi H., Hurme, Mikko, Kähönen, Mika, Männistö, Satu, Perola, Markus, Lehtimäki, Terho, Raitakari, Olli, Kaprio, Jaakko, and Ollikainen, Miina

Subjects
BODY mass index, EPIGENETICS, NATURE & nurture, TWINS, ECOLOGICAL genetics
Abstract

Background: Obesity is a heritable complex phenotype that can increase the risk of age‐related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various "epigenetic clocks." Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely correlates with mortality. Objectives: We aimed to assess the cross‐sectional association of body mass index (BMI) with age acceleration in twins to limit confounding by genetics and shared environment. Methods and results: Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twin pairs, and DNAm was measured using the Illumina 450K array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p‐value = 6.1 × 10–12) per one‐unit BMI increase. Additionally, heavier twins in a BMI‐discordant MZ twin pair (ΔBMI >3 kg/m2) had an epigenetic age 5.2 months older than their lighter cotwin (p‐value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta‐analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p‐value = 4.1 × 10–25) from adjusted models. Conclusion: We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Education as a moderator of middle-age cardiovascular risk factor—old-age cognition relationships: testing cognitive reserve hypothesis in epidemiological study.

Author

Iso-Markku, Paula, Kaprio, Jaakko, Lindgrén, Noora, Rinne, Juha O, and Vuoksimaa, Eero

Subjects
*CARDIOVASCULAR diseases risk factors, *TELEPHONES, *INTERVIEWING, *REGRESSION analysis, *RISK assessment, *QUESTIONNAIRES, *DEMENTIA, *BODY mass index, *COGNITIVE testing, *EDUCATIONAL attainment, *EPIDEMIOLOGICAL research, *PSYCHOLOGICAL resilience, *MIDDLE age, *OLD age
Abstract

Background higher educational attainment and less midlife cardiovascular risk factors are related to better old-age cognition. Whether education moderates the association between cardiovascular risk factors and late-life cognition is not known. We studied if higher education provides resilience against the deteriorative effects of higher middle-age body mass index (BMI) and a combination of midlife cardiovascular risk factors on old-age cognition. Methods the study population is the older Finnish Twin Cohort (n  = 4,051, mean age [standard deviation, SD] = 45.5 years [6.5]). Cardiovascular risk factors and education were studied at baseline with questionnaires in 1975, 1981 and/or 1990 (participation rates of 89, 84 and 77%, respectively). Cognition was evaluated with telephone interviews (participation rate 67%, mean age [SD] =73.4 [2.9] years, mean follow-up [SD] = 27.8 [6.0] years) in 1999–2017. We studied the main and interactive effects of education and BMI/dementia risk score on late-life cognition with linear regression analysis. The study design was formulated before the pre-defined analyses. Results years of education moderated the association between BMI with old-age cognition (among less educated persons, BMI-cognition association was stronger [ B  = −0.24 points per BMI unit, 95% CI −0.31, −0.18] than among more educated persons [ B  = −0.06 points per BMI unit, 95% CI −0.16, 0.03], P interaction < 0.01). There was a similar moderating effect of education on dementia risk score consisting of cardiovascular risk factors (P  < 0.001). Conclusions our results support the cognitive reserve hypothesis. Those with higher education may tolerate the deteriorative effects of midlife cardiovascular risk factors on old-age cognition better than those with lower education. [ABSTRACT FROM AUTHOR]

Published
2022
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41. Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

Author

Risner, Victoria A, Benca-Bachman, Chelsie E, Bertin, Lauren, Smith, Alicia K, Kaprio, Jaakko, McGeary, John E, Chesler, Elissa, Knopik, Valerie S, Friedman, Naomi P, and Palmer, Rohan H C

Subjects
NICOTINE addiction, GENOME-wide association studies, ALCOHOLISM, BODY mass index, GENEALOGY, SUBSTANCE abuse diagnosis, RESEARCH, SUBSTANCE abuse, SEQUENCE analysis, GENETICS, RESEARCH methodology, EVALUATION research, COMPARATIVE studies, RESEARCH funding, SMOKING
Abstract

Introduction: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.Methods: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µ age = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.Results: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.Conclusions: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.Implications: These findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences. [ABSTRACT FROM AUTHOR]

Published
2021
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42. The temporal relationship between parental concern of overeating and childhood obesity considering genetic susceptibility: longitudinal results from the IDEFICS/I.Family study.

Author

Masip, Guiomar, Foraita, Ronja, Silventoinen, Karri, Adan, Roger A. H., Ahrens, Wolfgang, De Henauw, Stefaan, Hebestreit, Antje, Keski-Rahkonen, Anna, Lissner, Lauren, Mehlig, Kirsten, Molnar, Dénés, Moreno, Luis A., Pigeot, Iris, Russo, Paola, Veidebaum, Toomas, Bogl, Leonie H., and Kaprio, Jaakko

Subjects
PARENT attitudes, FOOD habits, HYPERPHAGIA, CONFIDENCE intervals, CHILDHOOD obesity, GENETIC polymorphisms, RISK assessment, DESCRIPTIVE statistics, FACTOR analysis, WAIST circumference, QUESTIONNAIRES, BODY mass index
Abstract

Background: Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. Methods: The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean ± SD follow-up 5.8 ± 0.4). Children examined in 2007/2008 (wave 1) (mean ± SD age: 4.4 ± 1.1, range: 2–9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. Results: In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (β = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (β = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (β = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (β = 0.09, 95% CI: 0.07, 0.12). Conclusions: The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain. Trial registration: Registry number: ISRCTN62310987 Retrospectively registered 17 September 2018. [ABSTRACT FROM AUTHOR]

Published
2021
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43. Evaluation of the effect of donor weight on adipose stromal/stem cell characteristics by using weight-discordant monozygotic twin pairs.

Author

Juntunen, Miia, Heinonen, Sini, Huhtala, Heini, Rissanen, Aila, Kaprio, Jaakko, Kuismanen, Kirsi, Pietiläinen, Kirsi H., Miettinen, Susanna, and Patrikoski, Mimmi

Subjects
TWINS, STEM cells, BODY mass index, ADIPOSE tissues, ENDOTHELIAL cells
Abstract

Background: Adipose stromal/stem cells (ASCs) are promising candidates for future clinical applications. ASCs have regenerative capacity, low immunogenicity, and immunomodulatory ability. The success of future cell-based therapies depends on the appropriate selection of donors. Several factors, including age, sex, and body mass index (BMI), may influence ASC characteristics. Our aim was to investigate the effect of acquired weight on ASC characteristics under the same genetic background using ASCs derived from monozygotic (MZ) twin pairs. Methods: ASCs were isolated from subcutaneous adipose tissue from five weight-discordant (WD, within-pair difference in BMI > 3 kg/m2) MZ twin pairs, with measured BMI and metabolic status. The ASC immunophenotype, proliferation and osteogenic and adipogenic differentiation capacity were studied. ASC immunogenicity, immunosuppression capacity and the expression of inflammation markers were investigated. ASC angiogenic potential was assessed in cocultures with endothelial cells. Results: ASCs showed low immunogenicity, proliferation, and osteogenic differentiation capacity independent of weight among all donors. ASCs showed a mesenchymal stem cell-like immunophenotype; however, the expression of CD146 was significantly higher in leaner WD twins than in heavier cotwins. ASCs from heavier twins from WD pairs showed significantly greater adipogenic differentiation capacity and higher expression of TNF and lower angiogenic potential compared with their leaner cotwins. ASCs showed immunosuppressive capacity in direct cocultures; however, heavier WD twins showed stronger immunosuppressive capacity than leaner cotwins. Conclusions: Our genetically matched data suggest that a higher weight of the donor may have some effect on ASC characteristics, especially on angiogenic and adipogenic potential, which should be considered when ASCs are used clinically. [ABSTRACT FROM AUTHOR]

Published
2021
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44. Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs.

Author

Föhr, Tiina, Waller, Katja, Viljanen, Anne, Sanchez, Riikka, Ollikainen, Miina, Rantanen, Taina, Kaprio, Jaakko, and Sillanpää, Elina

Subjects
TWINS, SMOKING statistics, PROPORTIONAL hazards models, EPIGENETICS, AGE, PREMATURE aging (Medicine), MORTALITY, BODY mass index
Abstract

Background: Epigenetic clocks are based on DNA methylation (DNAm). It has been suggested that these clocks are useable markers of biological aging and premature mortality. Because genetic factors explain variations in both epigenetic aging and mortality, this association could also be explained by shared genetic factors. We investigated the influence of genetic and lifestyle factors (smoking, alcohol consumption, physical activity, chronic diseases, body mass index) and education on the association of accelerated epigenetic aging with mortality using a longitudinal twin design. Utilizing a publicly available online tool, we calculated the epigenetic age using two epigenetic clocks, Horvath DNAmAge and DNAm GrimAge, in 413 Finnish twin sisters, aged 63–76 years, at the beginning of the 18-year mortality follow-up. Epigenetic age acceleration was calculated as the residuals from a linear regression model of epigenetic age estimated on chronological age (AAHorvath, AAGrimAge, respectively). Cox proportional hazard models were conducted for individuals and twin pairs. Results: The results of the individual-based analyses showed an increased mortality hazard ratio (HR) of 1.31 (CI95: 1.13–1.53) per one standard deviation (SD) increase in AAGrimAge. The results indicated no significant associations of AAHorvath with mortality. Pairwise mortality analyses showed an HR of 1.50 (CI95: 1.02–2.20) per 1 SD increase in AAGrimAge. However, after adjusting for smoking, the HR attenuated substantially and was statistically non-significant (1.29; CI95: 0.84–1.99). Similarly, in multivariable adjusted models the HR (1.42–1.49) was non-significant. In AAHorvath, the non-significant HRs were lower among monozygotic pairs in comparison to dizygotic pairs, while in AAGrimAge there were no systematic differences by zygosity. Further, the pairwise analysis in quartiles showed that the increased within pair difference in AAGrimAge was associated with a higher all-cause mortality risk. Conclusions: In conclusion, the findings suggest that DNAm GrimAge is a strong predictor of mortality independent of genetic influences. Smoking, which is known to alter DNAm levels and is built into the DNAm GrimAge algorithm, attenuated the association between epigenetic aging and mortality risk. [ABSTRACT FROM AUTHOR]

Published
2021
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45. DO DISORDERED EATING BEHAVIORS HAVE LONG-TERM HEALTH-RELATED CONSEQUENCES?

Author

Kärkkäinen, Ulla, Mustelin, Linda, Raevuori, Anu, Kaprio, Jaakko, and Keski-Rahkonen, Anna

Subjects
Adult, Male, Overweight, Article, Body Mass Index, Feeding and Eating Disorders, Diagnostic Self Evaluation, Young Adult, Cross-Sectional Studies, Humans, Female, Prospective Studies, Waist Circumference, Stress, Psychological
Abstract

Long-term health-related consequences of disordered eating behaviours of young adults remain poorly understood. We examined whether disordered eating behaviours in mid-20s are associated with physical and mental health 10 years later.Women (n = 2631) and men (n = 2394) from a population-based FinnTwin16 cohort were assessed using three subscales of the Eating Disorder Inventory-2 at age 24. Self-rated health, body mass index (BMI), waist circumference and psychological distress were assessed at age 24 and reassessed 10 years later.In crude models, disordered eating behaviours at age 24 were associated cross-sectionally and prospectively with poor self-rated health, higher BMI, larger waist circumference and psychological distress in both sexes. In models adjusted for baseline BMI and potential confounders, disordered eating behaviours predicted increased psychological distress in both sexes and poor self-rated health in men.Among young adults, disordered eating behaviours are associated with long-term health-related consequences, particularly psychological distress. Copyright © 2017 John WileySons, Ltd and Eating Disorders Association.

Published
2017

46. Endotoxemia is associated with an adverse metabolic profile.

Author

Määttä, Anne-Mari, Salminen, Aino, Pietiäinen, Milla, Leskelä, Jaakko, Palviainen, Teemu, Sattler, Wolfgang, Sinisalo, Juha, Salomaa, Veikko, Kaprio, Jaakko, and Pussinen, Pirkko J

Subjects
ENDOTOXEMIA, HIGH density lipoproteins, CORONARY disease, BODY mass index, FETOFETAL transfusion, YOUNG adults
Abstract

Our aim was to analyze whether endotoxemia, i.e. translocation of LPS to circulation, is reflected in the serum metabolic profile in a general population and in participants with cardiometabolic disorders. We investigated three Finnish cohorts separately and in a meta-analysis (n = 7178), namely population-based FINRISK97, FinnTwin16 consisting of young adult twins, and Parogene, a random cohort of cardiac patients. Endotoxemia was determined as serum LPS activity and metabolome by an NMR platform. Potential effects of body mass index (BMI), smoking, metabolic syndrome (MetS), and coronary heart disease (CHD) status were considered. Endotoxemia was directly associated with concentrations of VLDL, IDL, LDL, and small HDL lipoproteins, VLDL particle diameter, total fatty acids (FA), glycoprotein acetyls (GlycA), aromatic and branched-chain amino acids, and Glc, and inversely associated with concentration of large HDL, diameters of LDL and HDL, as well as unsaturation degree of FAs. Some of these disadvantageous associations were significantly stronger in smokers and subjects with high BMI, but did not differ between participants with different CHD status. In participants with MetS, however, the associations of endotoxemia with FA parameters and GlycA were particularly strong. The metabolic profile in endotoxemia appears highly adverse, involving several inflammatory characters and risk factors for cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Obesity paradox in subarachnoid hemorrhage: a systematic review.

Author

Rautalin, Ilari, Kaprio, Jaakko, and Korja, Miikka

Subjects
*SUBARACHNOID hemorrhage, *MORBID obesity, *OBESITY, *BODY mass index, *HOSPITAL mortality
Abstract

As the number of obese people is globally increasing, reports about the putative protective effect of obesity in life-threatening diseases, such as subarachnoid hemorrhage (SAH), are gaining more interest. This theory—the obesity paradox—is challenging to study, and the impact of obesity has remained unclear in survival of several critical illnesses, including SAH. Thus, we performed a systematic review to clarify the relation of obesity and SAH mortality. Our study protocol included systematic literature search in PubMed, Scopus, and Cochrane library databases, whereas risk-of-bias estimation and quality of each selected study were evaluated by the Critical Appraisal Skills Program and Cochrane Collaboration guidelines. A directional power analysis was performed to estimate sufficient sample size for significant results. From 176 reviewed studies, six fulfilled our eligibility criteria for qualitative analysis. One study found paradoxical effect (odds ratio, OR = 0.83 (0.74–0.92)) between morbid obesity (body mass index (BMI) > 40) and in-hospital SAH mortality, and another study found the effect between continuously increasing BMI and both short-term (OR = 0.90 (0.82–0.99)) and long-term SAH mortalities (OR = 0.92 (0.85–0.98)). However, according to our quality assessment, methodological shortcomings expose all reviewed studies to a high-risk-of-bias. Even though two studies suggest that obesity may protect SAH patients from death in the acute phase, all reviewed studies suffered from methodological shortcomings that have been typical in the research field of obesity paradox. Therefore, no definite conclusions could be drawn. [ABSTRACT FROM AUTHOR]

Published
2020
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48. Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project

Author

Jelenkovic, Aline, Yokoyama, Yoshie, Sund, Reijo, Pietiläinen, Kirsi H, Hur, Yoon-Mi, Willemsen, Gonneke, Bartels, Meike, van Beijsterveldt, Toos CEM, Ooki, Syuichi, Saudino, Kimberly J., Antonietta Stazi, Maria, Fagnani, Corrado, D'Ippolito, Cristina, Nelson, Tracy L., Whitfield, Keith E., Knafo-noam, Ariel, Mankuta, David, Abramson, Lior, Heikkilä, Kauko, Cutler, Tessa L., Hopper, John L., Wardle, Jane, Llewellyn, Clare H., Fisher, Abigail, Corley, Robin P., Huibregtse, Brooke M., Derom, Catherine A, Vlietinck, Robert F., Loos, Ruth Jf, Bjerregaard-andersen, Morten, Beck-nielsen, Henning, Sodemann, Morten, Tarnoki, Adam D., Tarnoki, David L., Burt, S. Alexandra, Klump, Kelly L., Ordonana, Juan R., Sánchez-Romera, Juan F, Colodro-Conde, Lucía, Dubois, Lise, Boivin, Michel, Brendgen, Mara, Dionne, Ginette, Vitaro, Frank, Harris, Jennifer R, Brandt, Ingunn, Nilsen, Thomas Sevenius, Craig, Jeffrey M., Saffery, Richard, Rasmussen, Finn, Tynelius, Per, Bayasgalan, Gombojav, Narandalai, Danshiitsoodol, Haworth, Claire M, Plomin, Robert Joseph, Ji, Fuling, Ning, Feng, Pang, Zengchang, Rebato, Esther, Krueger, Robert F, McGue, Matt, Pahlen, Shandell, Boomsma, Dorret I., Sørensen , Thorkild IA, Kaprio, Jaakko, Silventoinen, Karri, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Department of Social Research (2010-2017), Centre for Social Data Science, CSDS, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Endokrinologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Department of Public Health, University of Helsinki, Sociology, Center for Population, Health and Society, Population Research Unit (PRU), HUS Abdominal Center, and Genetic Epidemiology

Subjects
Adult, Male, Netherlands Twin Register (NTR), Internationality, Adolescent, CHILDHOOD, INTRAUTERINE ENVIRONMENT, body mass index, Early Life and Obesity, Young Adult, Twins, Dizygotic, Medicine and Health Sciences, LENGTH, Journal Article, Birth Weight, Humans, ADULT DISEASE, LATE, Child, FETAL ORIGINS HYPOTHESIS, LATE ADOLESCENCE, OVERWEIGHT, Infant, Twins, Monozygotic, twins, Middle Aged, 3142 Public health care science, environmental and occupational health, birthweight, FAT, Child, Preschool, ADOLESCENCE, OBESITY, Linear Models, Female, ADIPOSITY
Abstract

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors.Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses.Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m 2 higher BMI ( P Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood.

Published
2017

49. The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children—Analyses based on path models

Author

Wolters, Maike, Dering, Carmen, Siani, Alfonso, Russo, Paola, Kaprio, Jaakko, Rise, Patrizia, Moreno, Luis A., De Henauw, Stefaan, Mehlig, Kirsten, Veidebaum, Toomas, Molnar, Denes, Tornaritis, Michael, Iacoviello, Licia, Pitsiladis, Yannis, Galli, Claudio, Foraita, Ronja, Bornhorst, Claudia, IDEFICS, I Family Consortia, Institute for Molecular Medicine Finland, University of Helsinki, and Genetic Epidemiology

Subjects
GENE-CLUSTER, ADIPOSE-TISSUE, QUALITY-CONTROL, PLASMA, ADOLESCENTS, CARDIOVASCULAR RISK-FACTORS, WHOLE-BLOOD, body mass index, childhood obesity, genetic polymorphism, blood pressure, human genetics, hypertension, fatty acids, cardiovascular diseases, lipids (amino acids, peptides, and proteins), DESATURASE ACTIVITIES, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, REFERENCE VALUES
Abstract

BACKGROUND: The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP. METHODS: A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to

Published
2017

50. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, Adam E, Kahali, Bratati, Croteau-Chonka, Damien C, Doney, Alex S F, He, Bing, Heikkilä, Outi, Hietala, Kustaa, Kytö, Janne, Lahermo, Päivi, Lehto, Markku, Österholm, Anne-May, Parkkonen, Maija, Pitkäniemi, Janne, Rosengård-Bärlund, Milla, Eklund, Niina, Saraheimo, Markku, Sarti, Cinzia, Söderlund, Jenny, Soro-Paavonen, Aino, Syreeni, Anna, Thorn, Lena M, Tikkanen, Heikki, Tolonen, Nina, Tryggvason, Karl, Tuomilehto, Jaakko, Estrada, Karol, Wadén, Johan, Gill, Geoffrey V, Prior, Sarah, Guiducci, Candace, Mirel, Daniel B, Taylor, Andrew, Hosseini, Mohsen, Parving, Hans-Henrik, Rossing, Peter, Tarnow, Lise, Eury, Elodie, Ladenvall, Claes, Alhenc-Gelas, François, Lefebvre, Pierre, Rigalleau, Vincent, Roussel, Ronan, Tregouet, David-Alexandre, Maestroni, Anna, Maestroni, Silvia, Falhammar, Henrik, Gu, Tianwei, Folkersen, Lasse, Möllsten, Anna, Cimponeriu, Dan, Mihai, Ioana, Mota, Maria, Mota, Eugen, Serafinceanu, Cristian, Stavarachi, Monica, Hanson, Robert L, Nelson, Robert G, Kretzler, Matthias, Fraser, Ross M, Colhoun, Helen M, Panduru, Nicolae Mircea, Gu, Harvest F, Brismar, Kerstin, Zerbini, Gianpaolo, Hadjadj, Samy, Marre, Michel, Groop, Leif, Lajer, Maria, Bull, Shelley B, Garcia, Melissa E, Waggott, Daryl, Paterson, Andrew D, Savage, David A, Bain, Stephen C, Martin, Finian, Hirschhorn, Joel N, Godson, Catherine, Florez, Jose C, Groop, Per-Henrik, Maxwell, Alexander P, Geller, Frank, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Giedraitis, Vilmantas, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Y, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Gigante, Bruna, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Esko, Tonu, Go, Alan S, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K E, Mangino, Massimo, Golay, Alain, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Goodall, Alison H, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Gordon, Scott D, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Gorski, Mathias, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doring, Angela, Elliott, Paul, Grabe, Hans-Jörgen, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John J P, Khaw, Kay-Tee, Kim, Eric, Grammer, Tanja B, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimaki, Terho, Lin, Shih-Yi, Lindstrom, Jaana, Loos, Ruth J F, Mach, François, McArdle, Wendy L, Gräßler, Jürgen, Meisinger, Christa, Mitchell, Braxton D, Muller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V M, Nsubuga, Rebecca N, Olafsson, Isleifur, Ong, Ken K, Palotie, Aarno, Grönberg, Henrik, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J, Reilly, Muredach P, Ridker, Paul M, Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Fall, Tove, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J, Tiret, Laurence, Uitterlinden, Andre G, van Pelt, L Joost, Vedantam, Sailaja, Gusto, Gaëlle, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H, Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F, Young, Elizabeth H, Zhao, Jing Hua, Adair, Linda S, Arveiler, Dominique, Haessler, Jeffrey, Assimes, Themistocles L, Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O, Boomsma, Dorret I, Borecki, Ingrid B, Bornstein, Stefan R, Bovet, Pascal, Burnier, Michel, Hall, Per, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chen, Yii-Der Ida, Collins, Francis S, Cooper, Richard S, Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B, Haller, Toomas, Ferrieres, Jean, Ferrucci, Luigi, Freimer, Nelson B, Gieger, Christian, Groop, Leif C, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B, Hingorani, Aroon, Hallmans, Goran, Hofman, Albert, Hovingh, G Kees, Hsiung, Chao Agnes, Humphries, Steve E, Hunt, Steven C, Hveem, Kristian, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Jula, Antti, Hartman, Catharina A, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S, Koudstaal, Peter J, Krauss, Ronald M, Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O, Hassinen, Maija, Laakso, Markku, Lakka, Timo A, Lind, Lars, Lindgren, Cecilia M, Martin, Nicholas G, März, Winfried, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D, Munroe, Patricia B, Njølstad, Inger, Pedersen, Nancy L, Power, Chris, Pramstaller, Peter P, Price, Jackie F, Psaty, Bruce M, Quertermous, Thomas, Heard-Costa, Nancy L, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K, Saramies, Jouko, Schwarz, Peter E H, Sheu, Wayne H-H, Shuldiner, Alan R, Siegbahn, Agneta, Spector, Tim D, Helmer, Quinta, Stefansson, Kari, Strachan, David P, Tayo, Bamidele O, Tremoli, Elena, Uusitupa, Matti, van Duijn, Cornelia M, Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J, Hengstenberg, Christian, Whitfield, John B, Wolffenbuttel, Bruce H R, Ordovas, Jose M, Boerwinkle, Eric, Palmer, Colin N A, Thorsteinsdottir, Unnur, Chasman, Daniel I, Rotter, Jerome I, Franks, Paul W, Ripatti, Samuli, Holmen, Oddgeir, Cupples, L Adrienne, Sandhu, Manjinder S, Rich, Stephen S, Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L, Ingelsson, Erik, Abecasis, Gonçalo R, Abecasis, Gonçalo, Hottenga, Jouke-Jan, Caulfield, Mark, Chasman, Dan, Ehret, Georg, Johnson, Andrew, Johnson, Louise, Larson, Martin, Levy, Daniel, James, Alan L, Munroe, Patricia, Newton-Cheh, Christopher, O'Reilly, Paul, Palmas, Walter, Psaty, Bruce, Rice, Kenneth, Smith, Albert, Snider, Harold, Tobin, Martin, Van Duijn, Cornelia, Jeff, Janina M, Verwoert, Germaine, Rice, Kenneth M, Johnson, Andrew D, Smith, Albert V, Tobin, Martin D, Verwoert, Germaine C, Hwang, Shih-Jen, Pihur, Vasyl, O'Reilly, Paul F, Amin, Najaf, Teumer, Alexander, Glazer, Nicole L, Launer, Lenore, Jolley, Jennifer, Aulchenko, Yurii, Heath, Simon, Sõber, Siim, Parsa, Afshin, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Juliusdottir, Thorhildur, Peden, John F, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N, Fava, Cristiano, Kinnunen, Leena, Fox, Ervin R, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Koenig, Wolfgang, Whincup, Peter H, Liu, Yongmei, Shi, Gang, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Lehtimäki, Terho, Matullo, Giuseppe, Koskenvuo, Markku, Gaunt, Tom R, Onland-Moret, N Charlotte, Cooper, Matthew N, Platou, Carl G P, Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Kratzer, Wolfgang, Braund, Peter S, Kuznetsova, Tatiana, Uiterwaal, Cuno S P M, Adeyemo, Adebowale, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D, Laitinen, Jaana, Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C, Steinle, Nanette I, Grobbee, Diederick E, Arking, Dan E, Kardia, Sharon L, Morrison, Alanna C, Lamina, Claudia, Najjar, Samer, Hadley, David, Brown, Morris J, Connell, John M, Hingorani, Aroon D, Day, Ian N M, Lawlor, Debbie A, Beilby, John P, Lawrence, Robert W, Leander, Karin, Clarke, Robert, Collins, Rory, Hopewell, Jemma C, Ongen, Halit, Dreisbach, Albert W, Li, Yali, Young, J. H., Bis, Joshua C, Viikari, Jorma, Lee, Nanette R, Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Lichtner, Peter, Frayling, Timothy M, Islam, Muhammad, Jafar, Tazeen H, Erdmann, Jeanette, Kulkarni, Smita R, Grässler, Jürgen, Howard, Philip, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Weder, Alan B, Lindström, Jaana, Sun, Yan V, Bergman, Richard N, Scott, Laura J, Stringham, Heather M, Peltonen, Leena, Vartiainen, Erkki, Brand, Stefan-Martin, Kutalik, Zoltán, Lo, Ken Sin, Staessen, Jan A, Wang, Thomas J, Burton, Paul R, Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K, Rudock, Megan E, Lobbens, Stéphane, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairajan, Tripathy, Vikal, Lorbeer, Roberto, Langefeld, Carl D, Rosengren, Annika, Thelle, Dag S, Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Salako, Tunde, Iwai, Naoharu, Lu, Yingchang, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H-Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Raffel, Leslie J, Yao, Jie, O'Donnell, Chris, Schwartz, Stephen M, Ikram, M Arfan, Longstreth, W. T., Mosley, Thomas H, Seshadri, Sudha, Mahajan, Anubha, Shrine, Nick R G, Wain, Louise V, Morken, Mario A, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A, Rasheed, Asif, Goel, Anuj, Watkins, Hugh, Bakker, Stephan J L, van Gilst, Wiek H, Janipalli, Charles S, Mani, K Radha, Yajnik, Chittaranjan S, McLachlan, Stela, Mattace-Raso, Francesco U S, Oostra, Ben A, Demirkan, Ayse, Lakatta, Edward G, Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J, Menni, Cristina, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Ong, Rick Twee-Hee, Dörr, Marcus, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Galan, Pilar, Merger, Sigrun, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Zhai, Guangju, Meschia, James F, Nalls, Michael A, Sharma, Pankaj, Terzic, Janos, Kumar, M J Kranthi, Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E, Fowkes, F Gerald R, Charchar, Fadi J, Guo, Xiuqing, Milani, Lili, Rotimi, Charles, Bots, Michiel L, Brand, Eva, Samani, Nilesh J, Polasek, Ozren, Talmud, Philippa J, Nyberg, Fredrik, Laan, Maris, Moayyeri, Alireza, Palmer, Lyle J, van der Schouw, Yvonne T, Casas, Juan P, Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K, Wong, Tien Y, Tai, E Shyong, Monda, Keri L, Rao, Dabeeru C, Morris, Richard W, Dominiczak, Anna F, Marmot, Michael G, Miki, Tetsuro, Chandak, Giriraj R, Coresh, Josef, Navis, Gerjan, Han, Bok-Ghee, Zhu, Xiaofeng, Melander, Olle, Gyllensten, Ulf B, Mulas, Antonella, Wright, Alan F, Farrall, Martin, Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J G, Altshuler, David, Müller, Gabriele, Rettig, Rainer, Uda, Manuela, Witteman, Jacqueline C M, Vasan, Ramachandran S, Larson, Martin G, Järvelin, Marjo-Riitta, Musk, Arthur W, Caulfield, Mark J, Alizadeh, Behrooz Z, de Boer, Rudolf A, Mägi, Reedik, Boezen, H Marike, Bruinenberg, Marcel, Franke, Lude, Hillege, Hans L, van der Klauw, Melanie M, Ormel, Johan, Postma, Dirkje S, Rosmalen, Judith G M, Nöthen, Markus M, Slaets, Joris P, Stolk, Ronald P, Scott, Robert 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EN., Warrington, NM., Alavere, H., Barroso, I., Berenson, GS., Blackburn, H., Busonero, F., Chen, W., Couper, D., Easton, DF., Eriksson, J., Foroud, T., Geller, F., Hernandez, DG., Kilpeläinen, TO., Li, S., Melbye, M., Murray, JC., Murray, SS., Nelis, M., Ness, AR., Northstone, K., Peacock, M., Pennell, CE., Pharoah, P., Rafnar, T., Rice, JP., Ring, SM., Schork, NJ., Segrè, AV., Sovio, U., Srinivasan, SR., Tammesoo, ML., Tyrer, J., van Meurs JB., Weedon, MN., Wichmann, H., Young, L., Bierut, LJ., Boyd, HA., Econs, MJ., Van T'Hooft, Ferdinand M., Njølstad, Inger, Abecasis, Gonçalo R., Barroso, Inɥ, The MIGEN Consortium, Investigator, Casari, GIORGIO NEVIO, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Landsteiner Laboratory, Clinical Haematology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Locke, A, Kahali, B, Berndt, S, Justice, A, Pers, T, Day, F, Powell, C, Vedantam, S, Buchkovich, M, Yang, J, Croteau-Chonka, D, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, J, Winkler, T, Wood, A, Workalemahu, T, Faul, J, Smith, J, Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, A, Karjalainen, J, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, J, Bragg-Gresham, J, Buyske, S, Demirkan, A, Deng, G, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Goel, A, Gong, J, Jackson, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, 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Investigators, The MuTHER Consortium, The MIGen Consortium, The PAGE Consortium, The ReproGen Consortium, The GENIE Consortium, The International Endogene Consortium, Berndt, Sonja I, Justice, Anne E, Hyppönen, Elina Tuulikki, Epidemiology and Data Science, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes

Subjects
Male, LOCI, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Body Mass Index, Insulin Secretion, Insulin, Age Factor, Adiposity, ddc:616, Adipogenesis, Genetic Predisposition to Disease/genetics, Synapse, 3. Good health, Continental Population Group, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], GENOME-WIDE ASSOCIATIONPROVIDES INSIGHTSGLYCEMIC TRAITSLOCIMETAANALYSISVARIANTSINDIVIDUALSHIPPOCAMPALARCHITECTURETOPIRAMATE, ddc:500, Adipogenesis/genetics, Single Nucleotide/genetics, Age Factors, Continental Population Groups, Energy Metabolism, Europe, Female, Genetic Predisposition to Disease, Glutamic Acid, Humans, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Synapses, Genome-Wide Association Study, Multidisciplinary, genetics [Adiposity], Human, Socio-culturale, genetics [Energy Metabolism], ta3111, genetic, body mass index, obesity, SDG 3 - Good Health and Well-being, GLYCEMIC TRAITS, genetics [Continental Population Groups], Genetic variability, Polymorphism, GENOME-WIDE ASSOCIATION, genetics [Adipogenesis], METAANALYSIS, Genetic association, Adipogenesi, genetics [Quantitative Trait Loci], ta1184, metabolism [Glutamic Acid], ta1182, PATHWAYS, metabolism [Synapses], ta3121, medicine.disease, metabolism [Insulin], Adiposity/genetics, Clinical Medicine, Quantitative Trait Loci/genetics, Body mass index, HUMAN HEIGHT, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Synapses/metabolism, Medizin, Obesity/genetics, Bioinformatics, genetic basis, Obesity/metabolism, genetics [Obesity], body mass index (BMI), genetics [Genetic Predisposition to Disease], ethnology [Europe], 2. Zero hunger, Genetics, ARCHITECTURE, Genetics of obesity, Medicine (all), Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Insulin/metabolism/secretion, Glutamic Acid/metabolism, genetics [Polymorphism, Single Nucleotide], EXPRESSION, Insulin/metabolism, PROVIDES INSIGHTS, genetics [Racial Groups], Biology, Obesity/genetics/metabolism, Europe/ethnology, metabolism [Obesity], Mendelian randomization, medicine, Energy Metabolism/genetics, body mass, genetic analysis, obesity, Klinisk medicin
Abstract

Item does not contain fulltext Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for approximately 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015

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