Publications by authors named "Patrik K E Magnusson"

207 Publications

Long-Term Exposure to Transportation Noise and Risk of Incident Stroke: A Pooled Study of Nine Scandinavian Cohorts.

Environ Health Perspect 2021 Oct 4;129(10):107002. Epub 2021 Oct 4.

Department of Health Security, Finnish Institute for Health and Welfare, Kuopio, Finland.

Background: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse.

Objective: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population.

Methods: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution.

Results: During follow-up (), 11,056 stroke cases were identified. Road traffic noise () was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of () and ]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. ) (; 95% CI: 0.99, 1.27), but not with higher exposure (, ; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke.

Discussion: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise. https://doi.org/10.1289/EHP8949.
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http://dx.doi.org/10.1289/EHP8949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489401PMC
October 2021

Long-term exposure to low-level ambient air pollution and incidence of stroke and coronary heart disease: a pooled analysis of six European cohorts within the ELAPSE project.

Lancet Planet Health 2021 09;5(9):e620-e632

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM), nitrogen dioxide (NO), black carbon, and warm-season ozone (O) with the incidence of stroke and acute coronary heart disease.

Methods: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values.

Findings: From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8-19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM (hazard ratio 1·10 [95% CI 1·01-1·21] per 5 μg/m increase), NO (1·08 [1·04-1·12] per 10 μg/m increase), and black carbon (1·06 [1·02-1·10] per 0·5 10/m increase), whereas coronary heart disease incidence was only associated with NO (1·04 [1·01-1·07]). Warm-season O was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM and NO remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 μg/m for PM and 40 μg/m for NO.

Interpretation: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values.

Funding: Health Effects Institute.
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http://dx.doi.org/10.1016/S2542-5196(21)00195-9DOI Listing
September 2021

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Horm Behav 2021 Sep 3;136:105054. Epub 2021 Sep 3.

Psychology Department, University of Nevada Las Vegas, Nevada, USA.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.
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http://dx.doi.org/10.1016/j.yhbeh.2021.105054DOI Listing
September 2021

Long term exposure to low level air pollution and mortality in eight European cohorts within the ELAPSE project: pooled analysis.

BMJ 2021 09 1;374:n1904. Epub 2021 Sep 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Objective: To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines.

Design: Pooled analysis of eight cohorts.

Setting: Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries.

Participants: 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM), nitrogen dioxide, ozone, and black carbon.

Main Outcome Measures: Deaths due to natural causes and cause specific mortality.

Results: Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m in PM was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m an increase of 5 µg/m in PM was associated with 29.6% (14% to 47.4%) increase in natural deaths.

Conclusions: Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
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http://dx.doi.org/10.1136/bmj.n1904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409282PMC
September 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

The frequency of misattributed paternity in Sweden is low and decreasing: A nationwide cohort study.

J Intern Med 2021 Jul 20. Epub 2021 Jul 20.

Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.

Background: The occurrence of misattributed paternity has consequences throughout society with implications ranging from inheritance and royal succession to transplantation. However, its frequency in Sweden is unknown.

Objective: To estimate the contemporary frequency of misattributed paternity in Sweden.

Methods: The study was based on nationwide ABO blood group data and a nationwide register of familial relationships in Sweden. These data were analysed using both a frequentist Poisson model and the Bayesian Gibbs model. The conduct of the study was approved by the regional ethics committee in Stockholm, Sweden (reference numbers 2018/167-31 and 2019-04656).

Results: Nearly two million mother-father-offspring family units were included. Overall, the frequency of misattributed paternity was estimated at 1.7% in both models. Misattributed paternity was more common among parents with low educational levels, and has decreased over time to a current 1%.

Conclusions: The misattributed paternity rate is similar to the rates in other West-European populations. Apart from widespread societal implications, studies on heritability may consider misattributed paternity as a minor source of error.
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http://dx.doi.org/10.1111/joim.13351DOI Listing
July 2021

Long-term exposure to air pollution and liver cancer incidence in six European cohorts.

Int J Cancer 2021 Dec 14;149(11):1887-1897. Epub 2021 Aug 14.

Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the "Effects of low-level air pollution: A study in Europe" (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO ), particulate matter with diameter <2.5 μm (PM ), black carbon (BC), warm-season ozone (O ), and eight elemental components of PM (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 μg/m ), PM (1.12, 0.92-1.36 per 5 μg/m ), and BC (1.15, 1.00-1.33 per 0.5 10 /m) and liver cancer incidence. Associations with NO and BC persisted in two-pollutant models with PM . Most components of PM were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM or NO . Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.
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http://dx.doi.org/10.1002/ijc.33743DOI Listing
December 2021

Resource profile and user guide of the Polygenic Index Repository.

Nat Hum Behav 2021 Jun 17. Epub 2021 Jun 17.

McCourt School of Public Policy, Georgetown University, Washington, DC, USA.

Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs' prediction accuracies, we constructed them using genome-wide association studies-some not previously published-from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the 'additive SNP factor'. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available.
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http://dx.doi.org/10.1038/s41562-021-01119-3DOI Listing
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480PMC
March 2021

Long-term exposure to low-level air pollution and incidence of asthma: the ELAPSE project.

Eur Respir J 2021 06 4;57(6). Epub 2021 Jun 4.

Dept of Environmental Science, Aarhus University, Roskilde, Denmark.

Background: Long-term exposure to ambient air pollution has been linked to childhood-onset asthma, although evidence is still insufficient. Within the multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we examined the associations of long-term exposures to particulate matter with a diameter <2.5 µm (PM), nitrogen dioxide (NO) and black carbon (BC) with asthma incidence in adults.

Methods: We pooled data from three cohorts in Denmark and Sweden with information on asthma hospital diagnoses. The average concentrations of air pollutants in 2010 were modelled by hybrid land-use regression models at participants' baseline residential addresses. Associations of air pollution exposures with asthma incidence were explored with Cox proportional hazard models, adjusting for potential confounders.

Results: Of 98 326 participants, 1965 developed asthma during a mean follow-up of 16.6 years. We observed associations in fully adjusted models with hazard ratios of 1.22 (95% CI 1.04-1.43) per 5 μg·m for PM, 1.17 (95% CI 1.10-1.25) per 10 µg·m for NO and 1.15 (95% CI 1.08-1.23) per 0.5×10m for BC. Hazard ratios were larger in cohort subsets with exposure levels below the European Union and US limit values and possibly World Health Organization guidelines for PM and NO. NO and BC estimates remained unchanged in two-pollutant models with PM, whereas PM estimates were attenuated to unity. The concentration-response curves showed no evidence of a threshold.

Conclusions: Long-term exposure to air pollution, especially from fossil fuel combustion sources such as motorised traffic, was associated with adult-onset asthma, even at levels below the current limit values.
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http://dx.doi.org/10.1183/13993003.03099-2020DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight.

Hum Mol Genet 2021 Sep;30(19):1894-1905

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.
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http://dx.doi.org/10.1093/hmg/ddab121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444448PMC
September 2021

Long-Term Exposure to Fine Particle Elemental Components and Natural and Cause-Specific Mortality-a Pooled Analysis of Eight European Cohorts within the ELAPSE Project.

Environ Health Perspect 2021 04 12;129(4):47009. Epub 2021 Apr 12.

Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.

Background: Inconsistent associations between long-term exposure to particles with an aerodynamic diameter [fine particulate matter ()] components and mortality have been reported, partly related to challenges in exposure assessment.

Objectives: We investigated the associations between long-term exposure to elemental components and mortality in a large pooled European cohort; to compare health effects of components estimated with two exposure modeling approaches, namely, supervised linear regression (SLR) and random forest (RF) algorithms.

Methods: We pooled data from eight European cohorts with 323,782 participants, average age 49 y at baseline (1985-2005). Residential exposure to 2010 annual average concentration of eight components [copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn)] was estimated with Europe-wide SLR and RF models at a scale. We applied Cox proportional hazards models to investigate the associations between components and natural and cause-specific mortality. In addition, two-pollutant analyses were conducted by adjusting each component for mass and nitrogen dioxide () separately.

Results: We observed 46,640 natural-cause deaths with 6,317,235 person-years and an average follow-up of 19.5 y. All SLR-modeled components were statistically significantly associated with natural-cause mortality in single-pollutant models with hazard ratios (HRs) from 1.05 to 1.27. Similar HRs were observed for RF-modeled Cu, Fe, K, S, V, and Zn with wider confidence intervals (CIs). HRs for SLR-modeled Ni, S, Si, V, and Zn remained above unity and (almost) significant after adjustment for both and . HRs only remained (almost) significant for RF-modeled K and V in two-pollutant models. The HRs for V were 1.03 (95% CI: 1.02, 1.05) and 1.06 (95% CI: 1.02, 1.10) for SLR- and RF-modeled exposures, respectively, per , adjusting for mass. Associations with cause-specific mortality were less consistent in two-pollutant models.

Conclusion: Long-term exposure to V in was most consistently associated with increased mortality. Associations for the other components were weaker for exposure modeled with RF than SLR in two-pollutant models. https://doi.org/10.1289/EHP8368.
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http://dx.doi.org/10.1289/EHP8368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041432PMC
April 2021

Using national register data to estimate the heritability of periodontitis.

J Clin Periodontol 2021 06 29;48(6):756-764. Epub 2021 Mar 29.

Department of Odontology, Umeå University, Umeå, Sweden.

Aim: To identify whether periodontal traits derived from electronic dental records are biologically informative and heritable.

Materials And Methods: The study included 11,974 adult twins (aged 30-92 years) in the Swedish Twin Registry. Periodontal records from dental examinations were retrieved from a national register and used to derive continuous measures of periodontal health. A latent class approach was used to derive categorial measures of periodontal status. The correlation patterns in these traits were contrasted in monozygotic and dizygotic twin pairs using quantitative genetic models to estimate the heritability of the traits.

Results: For continuous traits, heritability estimates ranged between 41.5% and 48.3% with the highest estimates for number of missing tooth surfaces and rate of change in number of deep periodontal pockets (≥6 mm). For categorial traits, the latent class approach identified three classes (good periodontal health, mild periodontitis signs and severe signs of periodontitis) and there was a clear difference in the hazard for subsequent tooth loss between these three classes. Despite this, the class allocations were only slightly more heritable than a conventional dichotomous disease definition (45.2% vs. 42.6%).

Conclusions: Periodontitis is a moderately heritable disease. Quantitative periodontal traits derived from electronic records are an attractive target for future genetic association studies.
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http://dx.doi.org/10.1111/jcpe.13459DOI Listing
June 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 05 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
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http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Long-term exposure to fine particle elemental components and lung cancer incidence in the ELAPSE pooled cohort.

Environ Res 2021 02 2;193:110568. Epub 2020 Dec 2.

Statistics Denmark, Sejrøgade 11, 2100, Copenhagen, Denmark; Section of Epidemiology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Øster Farimagsgade 5, 1014, Copenhagen, Denmark. Electronic address:

Background: An association between long-term exposure to fine particulate matter (PM) and lung cancer has been established in previous studies. PM is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the "Effects of Low-level Air Pollution: A Study in Europe" (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM and lung cancer incidence.

Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants' baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status).

Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m PM K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m PM Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m PM S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m PM V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO). After adjustment for PM mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative.

Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM components may prove helpful in future lung cancer prevention strategies.
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http://dx.doi.org/10.1016/j.envres.2020.110568DOI Listing
February 2021

Long-term exposure to low-level air pollution and incidence of chronic obstructive pulmonary disease: The ELAPSE project.

Environ Int 2021 01 1;146:106267. Epub 2020 Dec 1.

Department of Environmental Science, Aarhus University, Roskilde, Denmark; Global Centre for Clean Air Research, University of Surrey, Guildford, United Kingdom.

Background: Air pollution has been suggested as a risk factor for chronic obstructive pulmonary disease (COPD), but evidence is sparse and inconsistent.

Objectives: We examined the association between long-term exposure to low-level air pollution and COPD incidence.

Methods: Within the 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE) study, we pooled data from three cohorts, from Denmark and Sweden, with information on COPD hospital discharge diagnoses. Hybrid land use regression models were used to estimate annual mean concentrations of particulate matter with a diameter < 2.5 µm (PM), nitrogen dioxide (NO), and black carbon (BC) in 2010 at participants' baseline residential addresses, which were analysed in relation to COPD incidence using Cox proportional hazards models.

Results: Of 98,058 participants, 4,928 developed COPD during 16.6 years mean follow-up. The adjusted hazard ratios (HRs) and 95% confidence intervals for associations with COPD incidence were 1.17 (1.06, 1.29) per 5 µg/m for PM, 1.11 (1.06, 1.16) per 10 µg/m for NO, and 1.11 (1.06, 1.15) per 0.5 10m for BC. Associations persisted in subset participants with PM or NO levels below current EU and US limit values and WHO guidelines, with no evidence for a threshold. HRs for NO and BC remained unchanged in two-pollutant models with PM, whereas the HR for PM was attenuated to unity with NO or BC.

Conclusions: Long-term exposure to low-level air pollution is associated with the development of COPD, even below current EU and US limit values and possibly WHO guidelines. Traffic-related pollutants NO and BC may be the most relevant.
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http://dx.doi.org/10.1016/j.envint.2020.106267DOI Listing
January 2021

Long-term low-level ambient air pollution exposure and risk of lung cancer - A pooled analysis of 7 European cohorts.

Environ Int 2021 01 13;146:106249. Epub 2020 Nov 13.

Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden. Electronic address:

Background/aim: Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence.

Methods: The "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO), fine particulate matter (PM), black carbon (BC), and ozone (O) to assign exposure to cohort participants' residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines.

Results: The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO, PM, BC and O (warm season) were 24.2 µg/m (19.5, 29.7), 15.4 µg/m (12.8, 17.3), 1.6 10m (1.3, 1.8), and 86.6 µg/m (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM (HR: 1.13, 95% CI: 1.05, 1.23 per 5 µg/m). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 µg/m. We did not observe associations between NO, BC or O and lung cancer incidence.

Conclusions: Long-term ambient PM exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines.
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http://dx.doi.org/10.1016/j.envint.2020.106249DOI Listing
January 2021

Genetic and environmental variation in educational attainment: an individual-based analysis of 28 twin cohorts.

Sci Rep 2020 07 29;10(1):12681. Epub 2020 Jul 29.

Washington State Twin Registry, Washington State University - Health Sciences Spokane, Spokane, WA, USA.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c = 0.31; 0.29-0.33 and c = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.
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http://dx.doi.org/10.1038/s41598-020-69526-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391756PMC
July 2020

Heritability of Oral Microbiota and Immune Responses to Oral Bacteria.

Microorganisms 2020 Jul 27;8(8). Epub 2020 Jul 27.

Department of Odontology, Umeå University, 901 87 Umeå, Sweden.

Maintaining a symbiotic oral microbiota is essential for oral and dental health, and host genetic factors may affect the composition or function of the oral microbiota through a range of possible mechanisms, including immune pathways. The study included 836 Swedish twins divided into separate groups of adolescents ( = 418) and unrelated adults ( = 418). Oral microbiota composition and functions of non-enzymatically lysed oral bacteria samples were evaluated using 16S rRNA gene sequencing and functional bioinformatics tools in the adolescents. Adaptive immune responses were assessed by testing for serum IgG antibodies against a panel of common oral bacteria in adults. In the adolescents, host genetic factors were associated with both the detection and abundance of microbial species, but with considerable variation between species. Host genetic factors were associated with predicted microbiota functions, including several functions related to bacterial sucrose, fructose, and carbohydrate metabolism. In adults, genetic factors were associated with serum antibodies against oral bacteria. In conclusion, host genetic factors affect the composition of the oral microbiota at a species level, and host-governed adaptive immune responses, and also affect the concerted functions of the oral microbiota as a whole. This may help explain why some people are genetically predisposed to the major dental diseases of caries and periodontitis.
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http://dx.doi.org/10.3390/microorganisms8081126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464143PMC
July 2020

Facets of individual-specific health signatures determined from longitudinal plasma proteome profiling.

EBioMedicine 2020 Jul 3;57:102854. Epub 2020 Jul 3.

Science for Life Laboratory, Department of Protein Science, KTH-Royal Institute of Technology, Tomtebodavägen 23, Stockholm 171 65, Sweden. Electronic address:

Background: Precision medicine approaches aim to tackle diseases on an individual level through molecular profiling. Despite the growing knowledge about diseases and the reported diversity of molecular phenotypes, the descriptions of human health on an individual level have been far less elaborate.

Methods: To provide insights into the longitudinal protein signatures of well-being, we profiled blood plasma collected over one year from 101 clinically healthy individuals using multiplexed antibody assays. After applying an antibody validation scheme, we utilized > 700 protein profiles for in-depth analyses of the individuals' short-term health trajectories.

Findings: We found signatures of circulating proteomes to be highly individual-specific. Considering technical and longitudinal variability, we observed that 49% of the protein profiles were stable over one year. We also identified eight networks of proteins in which 11-242 proteins covaried over time. For each participant, there were unique protein profiles of which some could be explained by associations to genetic variants.

Interpretation: This observational and non-interventional study identifyed noticeable diversity among clinically healthy subjects, and facets of individual-specific signatures emerged by monitoring the variability of the circulating proteomes over time. To enable more personal hence precise assessments of health states, longitudinal profiling of circulating proteomes can provide a valuable component for precision medicine approaches.

Funding: This work was supported by the Erling Persson Foundation, the Swedish Heart and Lung Foundation, the Knut and Alice Wallenberg Foundation, Science for Life Laboratory, and the Swedish Research Council.
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http://dx.doi.org/10.1016/j.ebiom.2020.102854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334812PMC
July 2020

Psychiatric Disorders Are Associated with Increased Risk of Sepsis Following a Cancer Diagnosis.

Cancer Res 2020 08 12;80(16):3436-3442. Epub 2020 Jun 12.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Psychiatric disorders and infections are both common comorbidities among patients with cancer. However, little is known about the role of precancer psychiatric disorders on the subsequent risk of sepsis as a complication of infections among patients with cancer. We conducted a cohort study of 362,500 patients with newly diagnosed cancer during 2006-2014 in Sweden. We used flexible parametric models to calculate the HRs of sepsis after cancer diagnosis in relation to precancer psychiatric disorders and the analyses were performed in two models. In model 1, analyses were adjusted for sex, age at cancer diagnosis, calendar period, region of residence, and type of cancer. In model 2, further adjustments were made for marital status, educational level, cancer stage, infection history, and Charlson Comorbidity Index score. During a median follow-up of 2.6 years, we identified 872 cases of sepsis among patients with cancer with precancer psychiatric disorders (incidence rate, IR, 14.8 per 1,000 person-years) and 12,133 cases among patients with cancer without such disorders (IR, 11.6 per 1000 person-years), leading to a statistically significant association between precancer psychiatric disorders and sepsis in both the simplified (HR, 1.31; 95% CI, 1.22-1.40) and full (HR, 1.26; 95% CI, 1.18-1.35) models. The positive association was consistently noted among patients with different demographic factors or cancer characteristics, for most cancer types, and during the entire follow-up after cancer diagnosis. Collectively, preexisting psychiatric disorders were associated with an increased risk of sepsis after cancer diagnosis, suggesting a need of heightened clinical awareness in this patient group. SIGNIFICANCE: These results call for extended prevention and surveillance of sepsis among patients with cancer with psychiatric comorbidities.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0502DOI Listing
August 2020

Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.

Clin Pharmacol Ther 2020 12 18;108(6):1195-1202. Epub 2020 Jul 18.

Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.
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http://dx.doi.org/10.1002/cpt.1927DOI Listing
December 2020

Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education.

Sci Rep 2020 05 14;10(1):7974. Epub 2020 May 14.

Department of Epidemiology, School of Public Health, Seoul National University, Seoul, 08826, Korea.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.
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http://dx.doi.org/10.1038/s41598-020-64883-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224277PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Association test using Copy Number Profile Curves (CONCUR) enhances power in rare copy number variant analysis.

PLoS Comput Biol 2020 05 4;16(5):e1007797. Epub 2020 May 4.

Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America.

Copy number variants (CNVs) are the gain or loss of DNA segments in the genome that can vary in dosage and length. CNVs comprise a large proportion of variation in human genomes and impact health conditions. To detect rare CNV associations, kernel-based methods have been shown to be a powerful tool due to their flexibility in modeling the aggregate CNV effects, their ability to capture effects from different CNV features, and their accommodation of effect heterogeneity. To perform a kernel association test, a CNV locus needs to be defined so that locus-specific effects can be retained during aggregation. However, CNV loci are arbitrarily defined and different locus definitions can lead to different performance depending on the underlying effect patterns. In this work, we develop a new kernel-based test called CONCUR (i.e., copy number profile curve-based association test) that is free from a definition of locus and evaluates CNV-phenotype associations by comparing individuals' copy number profiles across the genomic regions. CONCUR is built on the proposed concepts of "copy number profile curves" to describe the CNV profile of an individual, and the "common area under the curve (cAUC) kernel" to model the multi-feature CNV effects. The proposed method captures the effects of CNV dosage and length, accounts for the numerical nature of copy numbers, and accommodates between- and within-locus etiological heterogeneity without the need to define artificial CNV loci as required in current kernel methods. In a variety of simulation settings, CONCUR shows comparable or improved power over existing approaches. Real data analyses suggest that CONCUR is well powered to detect CNV effects in the Swedish Schizophrenia Study and the Taiwan Biobank.
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http://dx.doi.org/10.1371/journal.pcbi.1007797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224564PMC
May 2020

Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia.

Nat Commun 2020 04 15;11(1):1842. Epub 2020 Apr 15.

Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA.

Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
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http://dx.doi.org/10.1038/s41467-020-15707-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160146PMC
April 2020

Co-aggregation and heritability of organ-specific autoimmunity: a population-based twin study.

Eur J Endocrinol 2020 May;182(5):473-480

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objective: Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases.

Design: Prospective twin cohort study.

Methods: We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 diabetes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data.

Results: Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0.71) for Graves' disease to 0.97 (95% CI: 0.91-1.00) for Addison's disease.

Conclusions: Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.
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http://dx.doi.org/10.1530/EJE-20-0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182094PMC
May 2020

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Pharmacogenomics J 2020 12 21;20(6):770-783. Epub 2020 Feb 21.

Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.
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http://dx.doi.org/10.1038/s41397-020-0165-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674154PMC
December 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021
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