Publications
165 results found
Marttinen P, Pirinen M, Sarin A-P, et al., 2014, Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression, Bioinformatics, Vol: 30, Pages: 2026-2034, ISSN: 1367-4803
Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals.Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes ( XRCC4 and MTHFD2L ) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study.Availability and implementation: R-code freely available for download at http://users.ics.aalto.fi/pemartti/gene_metabolome/ .
Bolton JL, Hayward C, Direk N, et al., 2014, Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin, PLOS Genetics, Vol: 10, ISSN: 1553-7390
Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Buxton JL, Das S, Rodriguez A, et al., 2014, Multiple Measures of Adiposity Are Associated with Mean Leukocyte Telomere Length in the Northern Finland Birth Cohort 1966, PLOS One, Vol: 9, ISSN: 1932-6203
Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.
Graversen L, Sorensen TIA, Petersen L, et al., 2014, Stability of the Associations between Early Life Risk Indicators and Adolescent Overweight over the Evolving Obesity Epidemic, PLOS One, Vol: 9, ISSN: 1932-6203
Background: Pre- and perinatal factors and preschool body size may help identify children developing overweight, but these factors might have changed during the development of the obesity epidemic.Objective: We aimed to assess the associations between early life risk indicators and overweight at the age of 9 and 15 years at different stages of the obesity epidemic.Methods: We used two population-based Northern Finland Birth Cohorts including 4111 children born in 1966 (NFBC1966) and 5414 children born in 1985–1986 (NFBC1986). In both cohorts, we used the same a priori defined prenatal factors, maternal body mass index (BMI), birth weight, infant weight (age 5 months and 1 year), and preschool BMI (age 2–5 years). We used internal references in early childhood to define percentiles of body size (<50, 50–75, 75–90 and >90) and generalized linear models to study the association with overweight, according to the International Obesity Taskforce (IOTF) definitions, at the ages of 9 and 15 years.Results: The prevalence of overweight at the age of 15 was 9% for children born in 1966 and 16% for children born in 1986. However, medians of infant weight and preschool BMI changed little between the cohorts, and we found similar associations between maternal BMI, infant weight, preschool BMI, and later overweight in the two cohorts. At 5 years, children above the 90th percentile had approximately a 12 times higher risk of being overweight at the age of 15 years compared to children below the 50th percentile in both cohorts.Conclusions: The associations between early body size and adolescent overweight showed remarkable stability, despite the increase in prevalence of overweight over the 20 years between the cohorts. Using consequently defined internal percentiles may be a valuable tool in clinical practice.
Graversen L, Sorensen TIA, Petersen L, et al., 2014, Preschool Weight and Body Mass Index in Relation to Central Obesity and Metabolic Syndrome in Adulthood, PLOS One, Vol: 9, ISSN: 1932-6203
Background: If preschool measures of body size routinely collected at preventive health examinations are associated with adult central obesity and metabolic syndrome, a focused use of these data for the identification of high risk children is possible. The aim of this study was to test the associations between preschool weight and body mass index (BMI) and adult BMI, central obesity and metabolic alterations.Methods: The Northern Finland Birth Cohort 1966 (NFBC1966) (N = 4111) is a population-based cohort. Preschool weight (age 5 months and 1 year) and BMI (age 2–5 years) were studied in relation to metabolic syndrome as well as BMI, waist circumference, lipoproteins, blood pressure, and fasting glucose at the age of 31 years. Linear regression models and generalized linear regression models with log link were used.Results: Throughout preschool ages, weight and BMI were significantly linearly associated with adult BMI and waist circumference. Preschool BMI was inversely associated with high-density lipoprotein levels from the age of 3 years. Compared with children in the lower half of the BMI range, the group of children with the 5% highest BMI at the age of 5 years had a relative risk of adult obesity of 6.2(95% CI:4.2–9.3), of adult central obesity of 2.4(95% CI:2.0–2.9), and of early onset adult metabolic syndrome of 2.5(95% CI:1.7–3.8).Conclusions: High preschool BMI is consistently associated with adult obesity, central obesity and early onset metabolic syndrome. Routinely collected measures of body size in preschool ages can help to identify children in need of focused prevention due to their increased risk of adverse metabolic alterations in adulthood.
Service SK, Teslovich TM, Fuchsberger C, et al., 2014, Re-sequencing Expands Our Understanding of the Phenotypic Impact of Variants at GWAS Loci, PLOS Genetics, Vol: 10, ISSN: 1553-7390
Genome-wide association studies (GWAS) have identified .500 common variants associated with quantitative metabolictraits, but in aggregate such variants explain at most 20–30% of the heritable component of population variation in thesetraits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in.6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 [NFBC]) and a type 2 diabetescase-control sample (The Finland-United States Investigation of NIDDM Genetics [FUSION] study). By sequencing the codingsequence and 59 and 39 untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits(serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting bothsingle-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotypeassociations at eight of these loci. At all eight of these loci, the identification of new associations provides significantevidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we foundsignificant gene-level evidence of association to non-synonymous variants with MAF,1%. Additionally, two potentiallydeleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094,a missense variant in LIPC) were considerably more common in these Finnish samples than in European referencepopulations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolatedpopulation, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotypedsamples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Taanila A, Ebeling H, Tiihala M, et al., 2014, Association Between Childhood Specific Learning Difficulties and School Performance in Adolescents With And Without ADHD Symptoms: A 16-Year Follow-Up, JOURNAL OF ATTENTION DISORDERS, Vol: 18, Pages: 61-72, ISSN: 1087-0547
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- Citations: 27
Sovio U, Kaakinen M, Tzoulaki I, et al., 2014, How do changes in body mass index in infancy and childhood associate with cardiometabolic profile in adulthood[quest] Findings from the Northern Finland Birth Cohort 1966 Study, Int J Obes, Vol: 38, Pages: 53-59, ISSN: 0307-0565
Saad NJ, Kaakinen M, Da Silva Couto Alves A, et al., 2013, Forced vital capacity, systemic inflammation and cardiometabolic markers in adulthood: a cross-sectional analysis, British Thoracic Society Winter Meeting 2013
Stephens SH, Hartz SM, Hoft NR, et al., 2013, Distinct Loci in the <i>CHRNA5</i>/<i>CHRNA3</i>/<i>CHRNB4</i> Gene Cluster Are Associated With Onset of Regular Smoking, GENETIC EPIDEMIOLOGY, Vol: 37, Pages: 846-859, ISSN: 0741-0395
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- Citations: 27
Do R, Willer CJ, Schmidt EM, et al., 2013, Common variants associated with plasma triglycerides and risk for coronary artery disease, Nature Genetics, Vol: 45, Pages: 1345-1352, ISSN: 1061-4036
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10−8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Willer CJ, Schmidt EM, Sengupta S, et al., 2013, Discovery and refinement of loci associated with lipid levels, Nature Genetics, Vol: 45, Pages: 1274-1283, ISSN: 1061-4036
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
Jaaskelainen A, Schwab U, Kolehmainen M, et al., 2013, Meal Frequencies Modify the Effect of Common Genetic Variants on Body Mass Index in Adolescents of the Northern Finland Birth Cohort 1986, PLOS One, Vol: 8, ISSN: 1932-6203
Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays –5 meals including breakfast (regular) and ≤4 meals with or without breakfast (meal skipping) – on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (<8 and ≥8 BMI-increasing alleles) groups was 0.90 (95% CI 0.63,1.17) kg/m2, whereas in regular eaters, this difference was 0.32 (95% CI 0.06,0.57) kg/m2 (pinteraction = 0.003). The effect of each MC4R rs17782313 risk allele on BMI in meal skippers (0.47 [95% CI 0.22,0.73] kg/m2) was nearly three-fold compared with regular eaters (0.18 [95% CI -0.06,0.41] kg/m2) (pinteraction = 0.016). Further, the per-allele effect of the FTO rs1421085 was 0.24 (95% CI 0.05,0.42) kg/m2 in regular eaters and 0.46 (95% CI 0.27,0.66) kg/m2 in meal skippers but the interaction between FTO genotype and meal frequencies on BMI was significant only in boys (pinteraction = 0.015). In summary, the regular five-meal pattern attenuated the increasing effect of common SNPs on BMI in adolescents. Considering the epidemic of obesity in youth, the promotion of regular eating may have substa
Saad NJ, Kaakinen M, Da Silva Couto Alves A, et al., 2013, Systemic inflammation and lung function in adulthood and their association with early life factors, European Respiratory Society 2013 Annual Congress
Bonnelykke K, Matheson MC, Pers TH, et al., 2013, Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization, NATURE GENETICS, Vol: 45, Pages: 902-U290, ISSN: 1061-4036
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- Citations: 192
Lagou V, Magi R, Marullo L, et al., 2013, Large-Scale Multi-Phenotype Meta-Analysis Evaluates Pleiotropic Effects on Cardiometabolic Factors and Risk for Type 2 Diabetes (T2D) at FTO, FADS1 and GIPR Loci, Publisher: AMER DIABETES ASSOC, Pages: A427-A428, ISSN: 0012-1797
Rietveld CA, Medland SE, Derringer J, et al., 2013, GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment, SCIENCE, Vol: 340, Pages: 1467-1471, ISSN: 0036-8075
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- Citations: 517
Fall T, Hagg S, Maegi R, et al., 2013, The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis, PLOS MEDICINE, Vol: 10, ISSN: 1549-1277
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- Citations: 145
Taal HR, St Pourcain B, Thiering E, et al., 2013, Common variants at 12q15 and 12q24 are associated with infant head circumference (vol 44, pg 532, 2012), NATURE GENETICS, Vol: 45, Pages: 713-713, ISSN: 1061-4036
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- Citations: 1
van der Loos MJHM, Rietveld CA, Eklund N, et al., 2013, The Molecular Genetic Architecture of Self-Employment, PLOS One, Vol: 8, ISSN: 1932-6203
Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable–entrepreneurship–that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg2/σP2 = 25%, h2 = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10−5 were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.
Vimaleswaran KS, Berry DJ, Lu C, et al., 2013, Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts, PLOS Medicine, Vol: 10, ISSN: 1549-1277
Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D i
Kantomaaa MT, Stamatakis E, Kankaanpaa A, et al., 2013, Physical activity and obesity mediate the association between childhood motor function and adolescents' academic achievement, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 1917-1922, ISSN: 0027-8424
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- Citations: 104
Cousminer DL, Berry DJ, Timpson NJ, et al., 2013, Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity, Human Molecular Genetics
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. While little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty, and cancer progression, pointing to shared underlying mechanisms.To discover genetic loci influencing pubertal height and growth and place them in context of overall growth and maturation, we performed genome-wide association (GWA) meta-analyses in up to 18,737 European samples utilizing longitudinally collected height measurements. We found significant associations (P<1.67 x 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased BMI, reduced pubertal growth, and earlier puberty.While epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty, and childhood obesity, and provides new information to pinpoint processes linking these traits.
Tyrrell J, Huikari V, Christie JT, et al., 2012, Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5CHRNA3CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight, Human Molecular Genetics, Vol: 21, Pages: 5344-5358, ISSN: 0964-6906
Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4–36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: −4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
Horikoshi M, Yaghootkar H, Mook-Kanamori DO, et al., 2012, New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism, Nature Genetics, Vol: 45, Pages: 76-82, ISSN: 1546-1718
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Morandi A, Meyre D, Lobbens S, et al., 2012, Estimation of Newborn Risk for Child or Adolescent Obesity: Lessons from Longitudinal Birth Cohorts, PLOS One, Vol: 7, ISSN: 1932-6203
Objectives: Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equationsestimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesityepidemic.Methods: We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equationsfor childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weightgain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. Weperformed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S.children.Results: In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescentobesity, and childhood obesity persistent into adolescence was good: AUROC = 0?78[0?74–0.82], 0?75[0?71–0?79] and0?85[0?80–0?90] respectively (all p,0?001). Adding the genetic score produced discrimination improvements #1%. TheNFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort(AUROC = 0?70[0?63–0?77] and 0?73[0?67–0?80] respectively) and the two additional equations for childhood obesity newlydrawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0?74[0?69–0?79] and0?79[0?73–0?84]) (all p,0?001). The three equations for childhood obesity were converted into simple Excel risk calculatorsfor potential clinical use.Conclusion: This study provides the first example of handy tools for predicting childhood obesity in newborns by means ofeasily recorded information, while it shows that currently known genetic variants have very little usefulness for suchprediction.
Yang J, Loos RJF, Powell JE, et al., 2012, <i>FTO</i> genotype is associated with phenotypic variability of body mass index, NATURE, Vol: 490, Pages: 267-+, ISSN: 0028-0836
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- Citations: 290
Kaakinen M, Ducci F, Sillanpaa MJ, et al., 2012, Associations between Variation in CHRNA5-CHRNA3-CHRNB4, Body Mass Index and Blood Pressure in the Northern Finland Birth Cohort 1966, PLOS One, Vol: 7, ISSN: 1932-6203
Background: The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation.Methodology/Principal Findings: We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by −1.21 (95% CI −2.01, −0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of −0.38 (−0.68, −0.08) kg/m2 per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing.Conclusions: Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible in
Graversen L, Sandbak A, Jarvellin MR, et al., 2012, Identification of preschool children at high risk of future overweight, Public Health Nutrition, Vol: 15, ISSN: 1368-9800
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