Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change
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Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change. / Würtz, Peter; Wang, Qin; Kangas, Antti J; Richmond, Rebecca C; Skarp, Joni; Tiainen, Mika; Tynkkynen, Tuulia; Soininen, Pasi; Havulinna, Aki S; Kaakinen, Marika; Viikari, Jorma S; Savolainen, Markku J; Kähönen, Mika; Lehtimäki, Terho; Männistö, Satu; Blankenberg, Stefan; Zeller, Tanja; Laitinen, Jaana; Pouta, Anneli; Mäntyselkä, Pekka; Vanhala, Mauno; Elliott, Paul; Pietiläinen, Kirsi H; Ripatti, Samuli; Salomaa, Veikko; Raitakari, Olli T; Järvelin, Marjo-Riitta; Smith, George Davey; Ala-Korpela, Mika.
in: PLOS MED, Jahrgang 11, Nr. 12, 12.2014, S. e1001765.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change
AU - Würtz, Peter
AU - Wang, Qin
AU - Kangas, Antti J
AU - Richmond, Rebecca C
AU - Skarp, Joni
AU - Tiainen, Mika
AU - Tynkkynen, Tuulia
AU - Soininen, Pasi
AU - Havulinna, Aki S
AU - Kaakinen, Marika
AU - Viikari, Jorma S
AU - Savolainen, Markku J
AU - Kähönen, Mika
AU - Lehtimäki, Terho
AU - Männistö, Satu
AU - Blankenberg, Stefan
AU - Zeller, Tanja
AU - Laitinen, Jaana
AU - Pouta, Anneli
AU - Mäntyselkä, Pekka
AU - Vanhala, Mauno
AU - Elliott, Paul
AU - Pietiläinen, Kirsi H
AU - Ripatti, Samuli
AU - Salomaa, Veikko
AU - Raitakari, Olli T
AU - Järvelin, Marjo-Riitta
AU - Smith, George Davey
AU - Ala-Korpela, Mika
PY - 2014/12
Y1 - 2014/12
N2 - BACKGROUND: Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.METHODS AND FINDINGS: We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).CONCLUSIONS: Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
AB - BACKGROUND: Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.METHODS AND FINDINGS: We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).CONCLUSIONS: Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
KW - Adiposity/physiology
KW - Adult
KW - Body Mass Index
KW - Body Weight/physiology
KW - Cross-Sectional Studies
KW - Female
KW - Humans
KW - Male
KW - Mendelian Randomization Analysis/methods
KW - Young Adult
U2 - 10.1371/journal.pmed.1001765
DO - 10.1371/journal.pmed.1001765
M3 - SCORING: Journal article
C2 - 25490400
VL - 11
SP - e1001765
JO - PLOS MED
JF - PLOS MED
SN - 1549-1277
IS - 12
ER -
