Publications
976 results found
Sliz E, Kettunen J, Holmes MV, et al., 2018, Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment, Circulation, Vol: 138, Pages: 2499-2512, ISSN: 0009-7322
Background:Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.Methods:Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.Results:Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2×10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels.Conclusions:Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid an
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Publisher correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits, Nature Genetics, Vol: 50, Pages: 1755-1755, ISSN: 1061-4036
Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.
Ligthart S, Vaez A, Vosa U, et al., 2018, Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders, American Journal of Human Genetics, Vol: 103, Pages: 691-706, ISSN: 0002-9297
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
Ramsay H, Barnett JH, Murray GK, et al., 2018, Cognition, psychosis risk and metabolic measures in two adolescent birth cohorts, PSYCHOLOGICAL MEDICINE, Vol: 48, Pages: 2609-2623, ISSN: 0033-2917
Nasanen-Gilmore P, Sipola-Leppanen M, Tikanmaki M, et al., 2018, Lung function in adults born preterm, PLoS One, Vol: 13, Pages: 1-15, ISSN: 1932-6203
Very preterm birth, before the gestational age (GA) of 32 weeks, increases the risk of obstructed airflow in adulthood. We examined whether all preterm births (GA<37 weeks) are associated with poorer adult lung function and whether any associations are explained by maternal, early life/neonatal, or current life factors. Participants of the ESTER Preterm Birth Study, born between 1985 and 1989 (during the pre-surfactant era), at the age of 23 years participated in a clinical study in which they performed spirometry and provided detailed medical history. Of the participants, 139 were born early preterm (GA<34 weeks), 239 late preterm (GA: 34-<37 weeks), and 341 full-term (GA≥37 weeks). Preterm birth was associated with poorer lung function. Mean differences between individuals born early preterm versus full-term were -0.23 standard deviation (SD) (95% confidence interval (CI): -0.40, -0.05)) for forced vital capacity z-score (zFVC), -0.44 SD (95% CI -0.64, -0.25) for forced expiratory volume z-score (zFEV1), and -0.29 SD (95% CI -0.47, -0.10) for zFEV1/FVC. For late preterm, mean differences with full-term controls were -0.02 SD (95% CI -0.17, 0.13), -0.12 SD (95% CI -0.29, 0.04) and -0.13 SD (95% CI -0.29, 0.02) for zFVC, zFEV1, and zFEV1/FVC, respectively. Examination of finer GA subgroups suggested an inverse non-linear association between lung function and GA, with the greatest impact on zFEV1 for those born extremely preterm. The subgroup means were GA<28 weeks: -0.98 SD; 28-<32 weeks: -0.29 SD; 32-<34 weeks: -0.44 SD; 34-<36 weeks: -0.10 SD; 36-<37weeks: -0.11 SD; term-born controls (≥37weeks): 0.02 SD. Corresponding means for zFEV1/FVC were -1.79, -0.44, -0.47, -0.48, -0.29, and -0.02. Adjustment for maternal pregnancy conditions and socioeconomic and lifestyle factors had no major impact on the relationship. Preterm birth is associated with airflow limitation in adult life. The association appears to be attributable predominantly
Macare C, Ducci F, Zhang Y, et al., 2018, A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response, European Neuropsychopharmacology, Vol: 28, Pages: 1103-1114, ISSN: 0924-977X
The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.
Balkhiyarova Z, Kaakinen MA, Draisma HHM, et al., 2018, Dissecting shared pathophysiology of type 2 diabetes and depressive symptoms using multi-phenotype genome-wide association study, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S128-S128, ISSN: 0012-186X
Kaakinen M, Prelot L, Draisma H, et al., 2018, Machine learning in multi-omics data to assess longitudinal predictors of glycaemic trait levels, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 709-709, ISSN: 0741-0395
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Draisma H, Kaakinen M, Prelot L, et al., 2018, Epigenome-wide association study of change in body mass index from young- to middle adulthood in 626 northern Finland birth cohort 1966 participants, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 724-725, ISSN: 0741-0395
Karhunen V, Wiklund P, Jarvelin M-R, et al., 2018, Joint genetic factors of body mass index and ADHD components, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 709-709, ISSN: 0741-0395
Anasanti MD, Kaakinen M, Jarvelin M-R, et al., 2018, Addressing the missing data issue in multi-phenotype genome-wide association studies, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 686-686, ISSN: 0741-0395
Ramzi NH, Yiorkas AM, Sebert S, et al., 2018, Relationship between BMI and emotion-handling capacity in an adult Finnish population: the Northern Finland Birth Cohort 1966, PLoS ONE, Vol: 13, ISSN: 1932-6203
BackgroundAlexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period.MethodsParticipants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated.ResultsBMI was significantly and positively associated with TAS-20 score (p<0.0001, both at 31 years and at 46 years of ages). The association remained statistically significant after adjustment for potential confounders (sex, marital status and several socio-economic indicators). In individuals who experienced the greatest change in BMI (in either direction) over the 15-year period, there was a modest mean increase in TAS-20 score.ConclusionsOur data revealed that TAS-20 score was correlated with and co-varied with body mass status. We suggest that future clinical research should consider the role of alexithymia in obesity. Further investigation of this relationship is warranted to ensure that the needs of obese subjects with undiagnosed alexithymia are considered in the design of weight management programmes.
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Genetic analysis of over one million people identifies 535 new loci associated with blood pressure traits, Nature Genetics, Vol: 50, Pages: 1412-1425, ISSN: 1061-4036
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
Wielscher M, Amaral AFS, Jarvelin M, et al., 2018, SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts, Respiratory Research, Vol: 19, ISSN: 1465-9921
BackgroundThe pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort.MethodsDNA methylation using Illumina Infinium Human Methylation 450 k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models.ResultsMethylation at cg08257009 in the SERPINA gene cluster, located 32 kb downstream of SERPINA1, not annotated to a gene, was associated with FEV1/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing.ConclusionsThe results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.
Lowry E, Rautio N, Karhunen V, et al., 2018, Understanding the complexity of glycaemic health - Systematic bio-psychosocial modelling of fasting glucose in middle-age adults; a DynaHEALTH study, International Journal of Obesity, Vol: 43, Pages: 1181-1192, ISSN: 0307-0565
Abstract BackgroundThe prevention of the risk of type 2 diabetes (T2D) is complicated by multidimensional interplays between biological and psychosocial factors acting at the individual level. To address the challenge we took a systematic approach, to explore the bio-psychosocial predictors of blood glucose in mid-age.MethodsBased on the 31- and 46-year follow-ups (5,078 participants, 43% male) of Northern Finland Birth Cohort 1966, we used a systematic strategy to select bio-psychosocial variables at 31 years to enable a data-driven approach. As selection criteria, the variable must be i) a component of the metabolic syndrome or an indicator of psychosocial health using WHO guidelines, ii) easily obtainable in general health check-ups and iii) associated with fasting blood glucose at 46 years (p<0.10). Exploratory and confirmatory factor analysis were used to derive latent factors, and stepwise linear regression allowed exploration of relationships between factors and fasting glucose.ResultsOf all 26 variables originally considered, 19 met selection criteria and were included in an exploratory factor analysis. Two variables were further excluded due to low loading (<0.3). We derived four latent factors, which we named as socioeconomic, metabolic, psychosocial and blood pressure status. The combination of metabolic and psychosocial factors, adjusted for sex, provided best prediction of fasting glucose at 46 years (explaining 10.7% of variation in glucose; P<0.001). Regarding different bio-psychosocial pathways and relationships, the importance of psychosocial factors in addition to established metabolic risk factors was highlighted.ConclusionsThe present study supports evidence for the bio-psychosocial nature of adult glycemic health and exemplifies an evidence-based approach to model the bio-psychosocial relationships. The factorial model may help further research and public health practice in focusing also on psychosocial aspects in maintaining normoglyca
Waage J, Standl M, Curtin JA, et al., 2018, Author correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis, Nature Genetics, ISSN: 1061-4036
In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
Waage J, Standl M, Curtin JA, et al., 2018, Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis, Nature Genetics, Vol: 50, Pages: 1072-1080, ISSN: 1061-4036
Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, and with increasing incidence in westernized countries.1,2 To elucidate the genetic architecture and understand disease mechanisms of allergic rhinitis, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implied genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants of importance for antigen binding. We further performed GWASs of allergic sensitization against inhalant allergens and non-allergic rhinitis suggesting shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
Yang Y, Zhao H, Boomsma DI, et al., 2018, Molecular genetic overlap between migraine and major depressive disorder., Eur J Hum Genet, Vol: 26, Pages: 1202-1216
Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (PSNP ≤ 5 × 10-8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome-wide significance threshold (PFisher's-combined ≤ 3.6 × 10-6). Pathway analysis of genes with PFisher's-combined ≤ 1 × 10-3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.
Lee JJ, Wedow R, Okbay A, et al., 2018, Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals, NATURE GENETICS, Vol: 50, Pages: 1112-+, ISSN: 1061-4036
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Laru J, Nedelec R, Ojaniemi M, et al., 2018, Childhood and adolescence body mass index associates with impaired reproductive function - a prospective, population-based cohort study, 34th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 448-449, ISSN: 0268-1161
Karjula S, Morin-Papunen L, Auvinen J, et al., 2018, Long-term health related quality of life (HRQoL), life satisfaction and health status in women with PCOS-a population-based follow-up analysis at ages 31 and 46, 34th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 444-445, ISSN: 0268-1161
Aslibekyan S, Agha G, Colicino E, et al., 2018, Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor alpha, JAMA CARDIOLOGY, Vol: 3, Pages: 463-472, ISSN: 2380-6583
Importance Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision.Objective To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings.Design, Setting, and Participants This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events.Exposures Circulating TNF-α concentration.Main Outcomes and Measures DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease.Results The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = −0.01 [0.003]; P = 7.36 × 10−8), cg08122652 (β [SE] = −0.008 [0.002]; P = 2.24 × 10−7), and cg22930808(β [SE] = −0.01 [0.002]; P = 6.92 × 10−8); NLRC5 at cg16411857 (β [SE] = −0.01 [0.002]; P = 2.14 × 10−13) and cg07839457 (β [SE] = −0.02 [0.003]; P = 6.31 ×
Savolainen J, Eisman A, Mason WA, et al., 2018, Socioeconomic disadvantage and psychological deficits: pathways from early cumulative risk to late-adolescent criminal conviction, Journal of Adolescence, Vol: 65, Pages: 16-24, ISSN: 0140-1971
Early exposure to multiple risk factors has been shown to predict criminal offending, but the mechanisms responsible for this association are poorly understood. Integrating social-environmental and dispositional theories of crime this research investigated the capacity of family socioeconomic disadvantage and individual psychological deficits to mediate the association between childhood cumulative risk and late adolescent criminal convictions. Male participants in the 1986 Northern Finland Birth Cohort Study (n = 3414) were followed from the prenatal period through age 19–20. The data were analyzed by estimating a structural equation model of the hypothesized pathways. The results found support for both processes of influence, and the model sustained a statistically significant direct effect of cumulative risk on crime. Socioeconomic disadvantage and psychological deficits contribute to criminal offending independently and with roughly equal magnitude. The results point to the utility of both environmental and psychological interventions to prevent criminality among children at risk.
Nedelec R, Jokelainen J, Miettunen J, et al., 2018, Early determinants of metabolically healthy obesity in young adults: study of the Northern Finland Birth Cohort 1966, International Journal of Obesity, Vol: 42, Pages: 1704-1714, ISSN: 0307-0565
BACKGROUND: A body of literature suggests a metabolically healthy phenotype in individuals with obesity. Despite important clinical implications, the early origins of metabolically healthy obesity (MHO) have received little attention. OBJECTIVE: To assess the prevalence of MHO among the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years of age, examine its determinants in early life taking into account the sex specificity. METHODS: We studied 3205 term-born cohort participants with data available for cardio-metabolic health outcomes at 31 years, and longitudinal height and weight data. After stratifying the population by sex, adult BMI and a strict definition of metabolic health (i.e., no risk factors meaning metabolic health), we obtained six groups. Repeated childhood height and weight measures were used to model early growth and early adiposity phenotypes. We employed marginal means adjusted for mother and child covariates including socio-economic status, birth weight and gestational-age, to compare differences between the groups. RESULTS: The prevalence of adult MHO was 6% in men and 13.5% in women. Differences in adult metabolic status were linked to alterations in BMI and age at adiposity peak in infancy (p < 0.0003 in men and p = 0.027 in women), and BMI and age at adiposity rebound (AR) (p < 0.0001 irrespective of sex). Compared to MHO, metabolically unhealthy obese (MUO) women were five and a half months younger at AR (p = 0.007) with a higher BMI while MUO men were four months older (p = 0.036) with no difference in BMI at AR. CONCLUSION: At the time of AR, MHO women appeared to be older than their MUO counterparts while MHO men were younger. These original results support potential risk factors at the time of adiposity rebound linked to metabolic health in adulthood. These variations by sex warrant independent replication.
Gormley P, Kurki MI, Hiekkala ME, et al., 2018, Common variant burden contributes to the familial aggregation of migraine in 1,589 families, Neuron, Vol: 98, Pages: 743-753.e4, ISSN: 0896-6273
Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.
Zhou A, Taylor AE, Karhunen V, et al., 2018, Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants, Scientific Reports, Vol: 8, ISSN: 2045-2322
Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87; β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.
Xu C-J, Soderhall C, Bustamante M, et al., 2018, DNA methylation in childhood asthma: an epigenome-wide meta-analysis, LANCET RESPIRATORY MEDICINE, Vol: 6, Pages: 379-388, ISSN: 2213-2600
BackgroundDNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.MethodsWe did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.Findings27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10−7) after meta-analysi
Teslovich TM, Kim DS, Yin X, et al., 2018, Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study, HUMAN MOLECULAR GENETICS, Vol: 27, Pages: 1664-1674, ISSN: 0964-6906
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Warrington NM, Richmond R, Fenstra B, et al., 2018, Maternal and fetal genetic contribution to gestational weight gain, International Journal of Obesity, Vol: 42, Pages: 775-784, ISSN: 0307-0565
Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and
Kaseva N, Vaarasmaki M, Matinolli H-M, et al., 2018, Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later: evidence from two birth cohort studies, INTERNATIONAL JOURNAL OF OBESITY, Vol: 42, Pages: 872-879, ISSN: 0307-0565
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- Citations: 36
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