| 41. |
- Hägg, Sara, et al.
(författare)
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Adiposity as a cause of cardiovascular disease : a Mendelian randomization study
- 2015
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 44:2, s. 578-586
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.
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| 42. |
- Jelenkovic, Aline, et al.
(författare)
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Associations between birth size and later height from infancy through adulthood : An individual based pooled analysis of 28 twin cohorts participating in the CODATwins project
- 2018
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Ingår i: Early Human Development. - : Elsevier BV. - 0378-3782 .- 1872-6232. ; 120, s. 53-60
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14–4.25 cm and 0.18–0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight.
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| 43. |
- Johannesson, Magnus, et al.
(författare)
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Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence
- 2017
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718.
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Tidskriftsartikel (refereegranskat)abstract
- Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P −8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P −6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10−6). Despite the well-known difference in twin-based heritability2 for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10−29). These findings provide new insight into the genetic architecture of intelligence.
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| 44. |
- Johannesson, Magnus, et al.
(författare)
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Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies
- 2017
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Ingår i: PLoS Genetics. - : Public Library of Science. - 1553-7404 .- 1553-7390. ; 13:1, s. 1-23
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called ‘missing heritability’. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51–62% in the number of genome-wide significant loci and a relative loss in polygenic score R2of 36–38%). Hence, cross-study heterogeneity contributes to the missing heritability.
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| 45. |
- Johannesson, Magnus, et al.
(författare)
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Polygenic risk scores for schizophrenia and bipolar disorder predict creativity
- 2015
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 18:7, s. 953-
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Tidskriftsartikel (refereegranskat)abstract
- We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 x 10(-6) and 3.8 x 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
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| 46. |
- Korek, Michal J., et al.
(författare)
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Traffic-related air pollution exposure and incidence of stroke in four cohorts from Stockholm
- 2015
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - : Springer Science and Business Media LLC. - 1559-0631 .- 1559-064X. ; 25:5, s. 517-523
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the risk of stroke related to long-term ambient air pollution exposure, in particular the role of various exposure time windows, using four cohorts from Stockholm County, Sweden. In total, 22,587 individuals were recruited from 1992 to 2004 and followed until 2011. Yearly air pollution levels resulting from local road traffic emissions were assessed at participant residences using dispersion models for particulate matter (PM10) and nitrogen oxides (NOX). Cohort-specific hazard ratios were estimated for time-weighted air pollution exposure during different time windows and the incidence of stroke, adjusted for common risk factors, and then meta-analysed. Overall, 868 subjects suffered a non-fatal or fatal stroke during 238,731 person-years of follow-up. An increment of 20 mu g/m(3) in estimated annual mean of road-traffic related NOX exposure at recruitment was associated with a hazard ratio of 1.16 (95% Cl 0.83-1.61), with evidence of heterogeneity between the cohorts. For PM10, an increment of 10 mu g/m(3) corresponded to a hazard ratio of 1.14(95% Cl 0.68-1.90). Time-window analyses did not reveal any clear induction-latency pattern. In conclusion, we found suggestive evidence of an association between long-term exposure to NOX and PM10 from local traffic and stroke at comparatively low levels of air pollution.
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| 47. |
- Kuja-Halkola, Ralf, et al.
(författare)
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Birth weight, sex, and celiac disease : a nationwide twin study
- 2017
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Ingår i: Clinical Epidemiology. - : DOVE Medical Press Ltd.. - 1179-1349 .- 1179-1349. ; 9, s. 567-577
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Earlier research suggests that birth weight may be associated with celiac disease (CD), but the direction of association has been unclear potentially due to confounding effect from genetic and intrafamilial factors. Through within-twin analyses, we aimed to minimize confounding effects such as twins that share genetic and early environmental exposures.Materials and methods: Using the Swedish Twin Registry, we examined the birth weight of 146,830 twins according to the CD status. CD was defined as having villous atrophy according to a small intestinal biopsy reports.Results: The prevalence of diagnosed CD was 0.5% (n=669), and we included 407 discordant pairs of CD-non-CD twins. Comparing the 669 CD patients with non-CD twins, the association between birth weight and future CD was not statistically significant (odds ratio [OR] per 1000 g increase in birth weight: 1.16; 95% confidence interval [CI]=0.97-1.38). In males, the association was positive and statistically significant (OR=1.50; 95% CI=1.11-2.02). However, the association was not significant in within-pair analyses for both dizygotic and monozygotic twins and for both sexes.Conclusion: This population-based study found that in male twins, higher birth weight was associated with higher risk of CD. However, when comparing discordant twin pairs in within-twin pair analyses, there was no statistically significant association between birth weight, intrauterine growth, and future risk of CD.
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| 48. |
- Kuja-Halkola, Ralf, et al.
(författare)
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Heritability of non-HLA genetics in coeliac disease : a population-based study in 107 000 twins
- 2016
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Ingår i: Gut. - London, United Kingdom : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 65:11, s. 1793-1798
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Almost 100% individuals with coeliac disease (CD) are carriers of the human leucocyte antigen (HLA) DQ2/DQ8 alleles. Earlier studies have, however, failed to consider the HLA system when estimating heritability in CD, thus violating an underlying assumption of heritability analysis. We examined the heritability of CD in a large population-based sample of twins, considering HLA.Design: In a population-representative sample of 107 912 twins, we identified individuals with CD (equal to villous atrophy) through biopsy reports from all Swedish pathology departments. We calculated concordance rates and tetrachoric correlations for monozygotic (MZ) and dizygotic (DZ) twin pairs. Further, we estimated heritability of CD, first strictly from observed data, and then the non-HLA heritability, representing the heritability of all genetic factors except the HLA locus, using an approach that circumvent the violation of underlying assumptions.Results: We identified 513 twins with a diagnosis of CD (prevalence 0.48%). Concordance rates were higher in MZ pairs (0.49) than in DZ pairs (0.10), as were tetrachoric correlations (0.89 in MZ vs 0.51 in DZ pairs). The heritability of CD was 75% (95% CI 55% to 96%). The non-HLA heritability was slightly attenuated, 68% (95% CI 40% to 96%), with shared (17%) and non-shared (15%) environmental factors explaining the remaining variability of CD.Conclusions: CD is characterised by a high heritability, but our study also suggests that non-shared environmental factors may be of importance to CD development. HLA seems to have only moderate impact on heritability estimates.
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| 49. |
- Magnusson, Patrik K. E., et al.
(författare)
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One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins
- 2016
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Ingår i: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 19:2, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Monozygotic (MZ) twins stem from the same single fertilized egg and therefore share all their inherited genetic variation. This is one of the unequivocal facts on which genetic epidemiology and twin studies are based. To what extent this also implies that MZ twins share genotypes in adult tissues is not precisely established, but a common pragmatic assumption is that MZ twins are 100% genetically identical also in adult tissues. During the past decade, this view has been challenged by several reports, with observations of differences in post-zygotic copy number variations (CNVs) between members of the same MZ pair. In this study, we performed a systematic search for differences of CNVs within 38 adult MZ pairs who had been misclassified as dizygotic (DZ) twins by questionnaire-based assessment. Initial scoring by PennCNV suggested a total of 967 CNV discor dances. The within-pair correlation in number of CNVs detected was strongly dependent on confidence score filtering and reached a plateau of r = 0.8 when restricting to CNVs detected with confidence score larger than 50. The top-ranked discordances were subsequently selected for validation by quantitative polymerase chain reaction (qPCR), from which one single similar to 120kb deletion in NRXN1 on chromosome 2 (bp 51017111-51136802) was validated. Despite involving an exon, no sign of cognitive/mental consequences was apparent in the affected twin pair, potentially reflecting limited or lack of expression of the transcripts containing this exon in nerve/brain.
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| 50. |
- Martin, Joanna, et al.
(författare)
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Copy number variation and neuropsychiatric problems in females and males in the general population
- 2019
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Ingår i: American Journal of Medical Genetics Part B. - : John Wiley & Sons. - 1552-4841 .- 1552-485X. ; 180:6, s. 341-350
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Tidskriftsartikel (refereegranskat)abstract
- Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex-specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100-500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex-specific effects. Medium deletions (OR[CI] = 1.18[1.05-1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19-1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14-3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45-9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.
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