[Show abstract][Hide abstract] ABSTRACT: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35,668 children from 20 studies in the discovery phase and 11,873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide-significance (P-value<5 x 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B, and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) (Standard Error (SE) 0.007), 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503, and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value=3.12 x 10(-10)) increase in childhood body mass index in a population of 1,955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
Human Molecular Genetics 11/2015; DOI:10.1093/hmg/ddv472 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Neighbourhood characteristics have been associated with health behaviours of residents. We used longitudinal data to examine whether neighbourhood characteristics (level of urbanization and socioeconomic status) are related to within-individual variations in health behaviours (alcohol consumption, smoking, exercise and self-interest in health) as people live in different neighbourhoods over time. METHODS: Participants were from the Young Finns prospective cohort study (N = 3145) with four repeated measurement times (1992, 2001, 2007 and 2011/2012). Neighbourhood socioeconomic status and level of urbanization were measured on the level of municipality and zip code area. Within-individual (i.e. fixed-effect) regression was used to examine whether these associations were observed within individuals who lived in different neighbourhood in different measurement times. RESULTS: People living in more urban zip code areas were more likely to smoke (b = 0.06; CI = 0.03-0.09) and drink alcohol (b = 0.11; CI = 0.08-0.14), and these associations were replicated in within-individual analysis-supporting social causation. Neighbourhood socioeconomic status and urbanization were associated with higher interest in maintaining personal health (b = 0.05; CI = 0.03-0.08 and b = 0.05; CI = 0.02-0.07, respectively), and these associations were also similar in within-individual analysis. Physical exercise was not associated with neighbourhood characteristics. CONCLUSIONS: These data lend partial support for the hypothesis that neighbourhood differences influence people's health behaviours.
The European Journal of Public Health 11/2015; DOI:10.1093/eurpub/ckv210 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertension may be predicted from childhood risk factors. Repeated observations of abnormal blood pressure in childhood may enhance prediction of hypertension and subclinical atherosclerosis in adulthood compared with a single observation. Participants (1927, 54% women) from the Cardiovascular Risk in Young Finns Study had systolic and diastolic blood pressure measurements performed when aged 3 to 24 years. Childhood/youth abnormal blood pressure was defined as above 90th or 95th percentile. After a 21- to 31-year follow-up, at the age of 30 to 45 years, hypertension (>140/90 mm Hg or antihypertensive medication) prevalence was found to be 19%. Carotid intima-media thickness was examined, and high-risk intima-media was defined as intima-media thickness >90th percentile or carotid plaques. Prediction of adulthood hypertension and high-risk intima-media was compared between one observation of abnormal blood pressure in childhood/youth and multiple observations by improved Pearson correlation coefficients and area under the receiver operating curve. When compared with a single measurement, 2 childhood/youth observations improved the correlation for adult systolic (r=0.44 versus 0.35, P<0.001) and diastolic (r=0.35 versus 0.17, P<0.001) blood pressure. In addition, 2 abnormal childhood/youth blood pressure observations increased the prediction of hypertension in adulthood (0.63 for 2 versus 0.60 for 1 observation, P=0.003). When compared with 2 measurements, third observation did not provide any significant improvement for correlation or prediction (P always >0.05). A higher number of childhood/youth observations of abnormal blood pressure did not enhance prediction of adult high-risk intima-media thickness. Compared with a single measurement, the prediction of adult hypertension was enhanced by 2 observations of abnormal blood pressure in childhood/youth.
[Show abstract][Hide abstract] ABSTRACT: Objective:
Age, education, and sex associate with cognitive performance. We investigated associations between age, sex, education, and cognitive performance in young or middle-aged adults and evaluated data reduction methods to optimally capture cognitive performance in our population-based data.
This study is part of the Cardiovascular Risk in Young Finns Study. The 3,596 randomly selected subjects (aged 3-18 years in 1980) have been followed up for 30 years. In 2011, a computer-based cognitive testing battery (the Cambridge Neuropsychological Test Automated Battery [CANTAB]) was used to assess several cognitive domains. Principal component analysis, categorical and standardized classifications were applied to the cognitive data.
Among 34- to 49-year-old participants, cognitive performance declined with age, while education associated with better cognitive functions in several cognitive domains. Men had higher performance on all cognitive domains except visual or episodic memory, in which women outperformed men. The results were similar regardless of the data reduction method used.
The associations between sex, age, education, and cognitive performance are already apparent in young adulthood or middle age. Principal component analyses, categorical and standardized classifications are useful tools to analyze CANTAB cognitive data. (PsycINFO Database Record
[Show abstract][Hide abstract] ABSTRACT: We used genome wide expression (GWE) data of circulating blood cells and pathway analysis to investigate the inflammatory and other molecular pathways that may be associated with long-standing depressive symptoms. Participants were 607 women and 316 men (mean age 42 years) from the Young Finns Study who participated in three consecutive study phases in 2001, 2007 and 2012. Using Gene-set enrichment analyses (GSEA) we focused our analyses to pathways (available in MSigDB database) that are likely to affect immunological and inflammatory processes. GSEA were performed for blood cell GWE data in 2012. Depressive symptoms were assessed using a modified 21-item Beck Depression Inventory in each of the three study phases. Participants who scored in the top quartile of depressive symptoms in each of the three measurement points (n = 191) differed from other participants (n = 732) in several gene-set pathways related to inflammatory processes or immune-inflammatory signaling including interleukin (IL-1) pathway, and pathways related to various immuno-inflammatory processes, such as toll-like, the NEF protein, the nuclear factor kB, the kinase AKT and the mature B cell antigen receptor pathway (false discovery rates, FDRs<0.12). The results provide novel genome wide molecular evidence that support the association between chronic depressive symptoms and altered immune-inflammatory regulation.
Journal of Psychiatric Research 10/2015; 71:120-125. DOI:10.1016/j.jpsychires.2015.09.017 · 3.96 Impact Factor
[Show description][Hide description] DESCRIPTION: A dominant approach to genetic association studies is to perform univariate tests between genotype- phenotype pairs. However, analysing related traits to- gether increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of in- dividual cohorts and restricted availability of individual- level genotype-phenotype data across the cohorts limit conducting multivariate tests.
We introduce metaCCA, a computational frame- work for summary statistics-based analysis of a single or multiple studies that allows multivariate represen- tation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algo- rithm to achieve robustness.
Multivariate meta-analysis of two Finnish studies
of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies.
Code is available at https://github.com/aalto-ics- kepaco.
bioRxiv preprint first posted online July 16, 2015;
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, men >50y, women 50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed signifi- cant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (!50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analy- sis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimor- phism of body shape.
[Show abstract][Hide abstract] ABSTRACT: Background:
It has been shown that higher education associates with health outcomes, but the less is known about the specific mechanisms mediating this association. We examined whether higher education would associate with long-term health transitions from childhood to adulthood and whether health behaviors, self-esteem, social support and work-related health hazards could mediate or confound this association.
The participants were from a population-based sample of 3596 men and women from the Young Finns study aged 3-18 years at the beginning of the study in 1980, and who responded to repeated surveys of educational attainment and self-rated health in four study phases from 1997 to 2012. The associations were tested using multistate Markov models for the health-state transition intensities.
Our results suggested that a 1-year difference in education was related to a 16% higher transition probability from mediocre to good self-rated health over the 5-year follow-up. Depressive symptoms and job strain seemed to partly mediate or confound the association, but self-esteem and social support did not.
These results suggest that educational attainment is associated with good self-rated health transitions from childhood to adulthood, and multiple processes rather than a single underlying mechanism are likely to drive the educational differences in self-rated health.
Journal of Public Health 09/2015; DOI:10.1093/pubmed/fdv124 · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70-0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.
[Show abstract][Hide abstract] ABSTRACT: High blood pressure, which affects more than 1 billion people worldwide , is a major risk factor for myocardial infarction, stroke and chronic kidney disease. Approximately 9 million deaths each year are attributable to high blood pressure, including >50% of deaths from coronary heart disease and stroke 1,2. High blood pressure is more prevalent in people of East Asian and South Asian ancestry and is a major contributor to their increased risk of stroke and coronary heart disease 3,4. Genome-wide association studies (GWAS) have identified over 50 genetic loci influencing blood pressure in predominantly European populations 5–16. A role for epigenetic mechanisms in blood pressure regulation has also been suggested 17–20. We carried out a GWAS in East Asians and South Asians, as well as Europeans, to seek both cosmopolitan and population-specific genetic effects for five blood pressure phenotypes: systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure, mean arterial pressure (MAP) and hypertension (Supplementary Fig. 1) (ref. 5). We then sought DNA coding and gene regulatory mechanisms, including DNA methylation and gene transcription, to help explain the relationships we observed between sequence variation and blood pressure. RESULTS Genome-wide association and replication testing We used genome-wide association data from 99,994 individuals of East Asian (n = 31,516), European (n = 35,352) and South Asian (n = 33,126) ancestry. Characteristics of the participants and information on the genotyping arrays and imputation are summarized in Supplementary Tables 1–3. Phenotype-specific meta-analysis was carried out separately for East Asian, European and South Asian samples, followed by a meta-analysis across the three ancestral population groups. The trans-ancestry genome-wide association results identified 4,077 variants with P < 1 × 10 −4 against any blood pressure phenotype, distributed among 630 genetic loci. At each locus, we identified the sentinel SNP (the SNP with the lowest P value against any phenotype) and carried out combined analysis with phenotype-specific results from the International Consortium on Blood Pressure (ICBP) GWAS (maximum n = 87,205) (refs. 8,9). This analysis identified 19 previously unreported loci where the sentinel SNP had suggestive evidence for association with blood pressure (P < 1 × 10 −7
[Show abstract][Hide abstract] ABSTRACT: The effect of acute mental stress on atherosclerosis can be estimated using arterial elasticity measured by carotid artery distensibility (Cdist). We examined the interactive effect of acute stress-induced cardiac reactivity and Cdist to preclinical atherosclerosis assessed by carotid intima-media thickness (IMT) in 58 healthy adults aged 24-39 years participated in the epidemiological Young Finns Study. Cdist and IMT were measured ultrasonographically. Impedance electrocardiography was used to measure acute mental stress-induced cardiac autonomic responses: heart rate (HR), respiratory sinus arrhythmia and pre-ejection period after the mental arithmetic and the public speaking tasks. Interactions between HR reactivity and Cdist in relation to preclinical atherosclerosis were found. The results imply that elevated HR reactivity to acute mental stress is related to less atherosclerosis among healthy participants with higher arterial elasticity. Possibly, increased cardiac reactivity in response to challenging tasks is an adaptive reaction related to better cardiovascular health.