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1. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Author

Kazuyoshi, Ishigaki, Saori, Sakaue, Chikashi, Terao, Yang, Luo, Kyuto, Sonehara, Kensuke, Yamaguchi, Tiffany, Amariuta, Chun Lai, Too, Vincent A, Laufer, Ian C, Scott, Sebastien, Viatte, Meiko, Takahashi, Koichiro, Ohmura, Akira, Murasawa, Motomu, Hashimoto, Hiromu, Ito, Mohammed, Hammoudeh, Samar Al, Emadi, Basel K, Masri, Hussein, Halabi, Humeira, Badsha, Imad W, Uthman, Xin, Wu, Li, Lin, Ting, Li, Darren, Plant, Anne, Barton, Gisela, Orozco, Suzanne M M, Verstappen, John, Bowes, Alexander J, MacGregor, Suguru, Honda, Masaru, Koido, Kohei, Tomizuka, Yoichiro, Kamatani, Hiroaki, Tanaka, Eiichi, Tanaka, Akari, Suzuki, Yuichi, Maeda, Kenichi, Yamamoto, Satoru, Miyawaki, Gang, Xie, Jinyi, Zhang, Christopher I, Amos, Edward, Keystone, Gertjan, Wolbink, Irene, van der Horst-Bruinsma, Jing, Cui, Katherine P, Liao, Robert J, Carroll, Hye-Soon, Lee, So-Young, Bang, Katherine A, Siminovitch, Niek, de Vries, Lars, Alfredsson, Solbritt, Rantapää-Dahlqvist, Elizabeth W, Karlson, Sang-Cheol, Bae, Robert P, Kimberly, Jeffrey C, Edberg, Xavier, Mariette, Tom, Huizinga, Philippe, Dieudé, Matthias, Schneider, Martin, Kerick, Joshua C, Denny, Koichi, Matsuda, Keitaro, Matsuo, Tsuneyo, Mimori, Fumihiko, Matsuda, Keishi, Fujio, Yoshiya, Tanaka, Atsushi, Kumanogoh, Matthew, Traylor, Cathryn M, Lewis, Stephen, Eyre, Huji, Xu, Richa, Saxena, Thurayya, Arayssi, Yuta, Kochi, Katsunori, Ikari, Masayoshi, Harigai, Peter K, Gregersen, Kazuhiko, Yamamoto, S, Louis Bridges, Leonid, Padyukov, Javier, Martin, Lars, Klareskog, Yukinori, Okada, Soumya, Raychaudhuri, AII - Inflammatory diseases, Experimental Immunology, Clinical Immunology and Rheumatology, Rheumatology, AMS - Musculoskeletal Health, and AMS - Tissue Function & Regeneration

Subjects
Arthritis, Rheumatoid, Asian People, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study, Adaptor Proteins, Signal Transducing
Abstract

Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Published
2022

2. Association of alcohol-induced loss of consciousness and overall alcohol consumption with risk for dementia

Author

Marie Zins, May A. Beydoun, Jane E. Ferrie, Séverine Sabia, Lars Alfredsson, Gill Livingston, Markus Jokela, Pyry N Sipilä, Mika Kivimäki, Solja T. Nyberg, Aki Koskinen, Marcel Goldberg, G. David Batty, Jaana Pentti, Archana Singh-Manoux, Peter Westerholm, Timo E. Strandberg, Anders Knutsson, Sakari Suominen, Jussi Vahtera, Ari Väänänen, Andrew Sommerlad, Joni V Lindbohm, Sarah Floud, Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Department of Psychology and Logopedics, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, and Helsinki University Hospital Area

Subjects
Male, Unconsciousness, SWEDISH, Cohort Studies, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, Finland, Original Investigation, DAMAGE, education.field_of_study, Hazard ratio, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Middle Aged, Alcoholism, Online Only, Female, France, Public Health, medicine.symptom, MIDLIFE, Cohort study, Adult, Adolescent, Population, Binge drinking, 03 medical and health sciences, mental disorders, medicine, Dementia, Humans, CORONARY-HEART-DISEASE, Risk factor, education, BINGE DRINKING, METAANALYSIS, Aged, Proportional Hazards Models, Sweden, DECLINE, Ethanol, Proportional hazards model, business.industry, Research, Klinisk medicin, medicine.disease, COGNITIVE IMPAIRMENT, LIFE-STYLE FACTORS, United Kingdom, Featured, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 3121 General medicine, internal medicine and other clinical medicine, Clinical Medicine, business, FOLLOW-UP, 030217 neurology & neurosurgery, Demography
Abstract

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

Published
2023

3. Response to Comment 'Sex-specific exposures and sex-combined outcomes in two-sample Mendelian randomization may mislead the causal inference' on 'Age at menarche, age at natural menopause, and risk of rheumatoid arthritis—a Mendelian randomization study'

Author

Jingjing Zhu, Zheng Niu, Lars Alfredsson, Lars Klareskog, Leonid Padyukov, and Xia Jiang

Subjects
Male, Menarche, Arthritis, Rheumatoid, Humans, Female, Mendelian Randomization Analysis, Menopause, Genome-Wide Association Study
Published
2022

4. High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development

Author

Lars Alfredsson, Anna Karin Hedström, Jing Wu, Tomas Olsson, Anna Fogdell-Hahn, Tim Waterboer, Rasmus Gustafsson, Jan Hillert, and Elin Engdahl

Subjects
0303 health sciences, Multiple Sclerosis, Human Herpesvirus 6A, Ultraviolet Rays, business.industry, Herpesvirus 6, Human, Multiple sclerosis, Antibody level, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Lifestyle factors, Neurology, Case-Control Studies, Immunology, Humans, Medicine, Neurology (clinical), business, Life Style, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied. Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale. Results: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4–1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1–0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1–0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0–0.6). Conclusion: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.

Published
2021

5. Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis

Author

Lars Alfredsson, Tomas Olsson, Jan Hillert, and Anna Karin Hedström

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Disease, Affect (psychology), Logistic regression, Young Adult, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Risk Factors, Internal medicine, Humans, Medicine, Snuff, Allele, Alleles, 030304 developmental biology, Sweden, 0303 health sciences, business.industry, Multiple sclerosis, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Phenotype, Obesity, Psychiatry and Mental health, Case-Control Studies, Female, Gene-Environment Interaction, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, HLA-DRB1 Chains
Abstract

ObjectiveIt has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS.MethodsWe used two Swedish population-based case–control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale.ResultsAll environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype.InterpretationOur finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.

Published
2021

6. Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study

Author

Lars Klareskog, Lars Alfredsson, Zheng Niu, Xia Jiang, Jingjing Zhu, and Leonid Padyukov

Subjects
lcsh:Diseases of the musculoskeletal system, Genome-wide association study, Single-nucleotide polymorphism, Age at natural menopause, Polymorphism, Single Nucleotide, Arthritis, Rheumatoid, Mendelian randomization, Humans, Medicine, Rheumatoid arthritis, Age at first birth, Socioeconomic status, Menarche, Age at menarche, business.industry, Confounding, Mendelian Randomization Analysis, Sample size determination, Etiology, Female, Menopause, lcsh:RC925-935, business, Research Article, Genome-Wide Association Study, Demography
Abstract

Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA. Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions. Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98–1.15]; ORper-SD increment in ANM = 1.05 [0.98–1.11], OR per-SD increment in AFB = 0.85 [0.65–1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97–1.15], ORper-SD increment in ANM = 1.05 [0.98–1.13], ORper-SD increment in AFB = 0.81 [0.61–1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94–1.12], ORper-SD increment in ANM = 1.04 [0.95–1.14]). No outlying instrument was identified through the leave-one-out analysis. Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

Published
2021

7. Neither low social support nor low decision latitude at work is associated with disease remission among patients with rheumatoid arthritis: results from the Swedish EIRA study

Author

Louise, Hedenstierna, Anna Karin, Hedström, Lars, Klareskog, Daniela, Di Giuseppe, Lars, Alfredsson, Johan, Askling, Sofia, Ernestam, Saedis, Saevarsdottir, and Lotta, Ljung

Subjects
Arthritis, Rheumatoid, Cohort Studies, Sweden, C-Reactive Protein, Antirheumatic Agents, Remission Induction, Humans, Social Support, Severity of Illness Index
Abstract

To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA).This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996-2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level.Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74-1.16), 12 (OR 0.96, 95%CI 0.75-1.23), or 60 (OR 0.89, 95%CI 0.72-1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54-1.31), 12 (OR 0.81, 95%CI 0.56-1.16), or 60 (OR 1.37, 95%CI 0.94-2.01) months.In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.

Published
2022

8. DRB1–environment interactions in multiple sclerosis etiology: results from two Swedish case–control studies

Author

Lars Alfredsson, Anna Karin Hedström, Ingrid Kockum, Pernilla Strid, Julia Butt, Tomas Olsson, Nicole Brenner, Jan Hillert, and Tim Waterboer

Subjects
Adult, Male, Multiple Sclerosis, Adolescent, Genotype, Population, Overweight, Logistic regression, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Registries, Allele, education, Alleles, 030304 developmental biology, Aged, Sweden, 0303 health sciences, education.field_of_study, business.industry, Case-control study, Middle Aged, medicine.disease, Obesity, Psychiatry and Mental health, Case-Control Studies, Surgery, Female, Gene-Environment Interaction, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Demography, HLA-DRB1 Chains
Abstract

ObjectiveWe aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01.MethodsUsing population-based case–control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.ResultsThe effect of each DRB1*15:01 allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01 and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01 alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01 carriers without the protective A*02:01 allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01 homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).ConclusionsThe strikingly increased MS risk among DRB*15:01 homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

Published
2021

9. The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: evidence from the MyEIRA case-control study

Author

Hussein Heselynn, Lars Alfredsson, Suk Chyn Gun, Mohamed Said Mohd-Shahrir, Mageswaran Eashwary, S. Wahinuddin, Leonid Padyukov, Shahril Nor-Shuhaila, Othman Muhaini, Lars Klareskog, Lay Kim Tan, Mohd Mokhtar Ainon, Rosman Azmillah, Lina-Marcela Diaz-Gallo, Murad Shahnaz, Ing Soo Lau, and Chun Lai Too

Subjects
0301 basic medicine, musculoskeletal diseases, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Population, Human leukocyte antigen, Biology, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, HLA fine-mapping, HLA Antigens, Epidemiology, medicine, Humans, Genetic Predisposition to Disease, Allele, Rheumatoid arthritis, education, Genotyping, Alleles, Autoantibodies, 030203 arthritis & rheumatology, education.field_of_study, Risk variants, Haplotype, Case-control study, medicine.disease, HLA amino acid residues, 030104 developmental biology, Case-Control Studies, Immunology, lcsh:RC925-935, Multi-ethnic Malaysian population, Research Article, HLA-DRB1 Chains
Abstract

Background Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. Methods We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. Results We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30–5.49, PGWAS = 7.22 × 10−29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37–0.62, PGWAS = 2.58 × 10−08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09–0.30, PGWAS = 1.60 × 10−09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. Conclusions Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

Published
2021

10. Swedish snus use is associated with mortality: a pooled analysis of eight prospective studies

Author

Per-Olof Östergren, Patrik Wennberg, Lars Alfredsson, Marie Eriksson, Marzieh Araghi, Marja Lisa Byhamre, Weimin Ye, Ylva Trolle Lagerros, Michael Lundberg, Jan-Håkan Jansson, Gunnar Engström, Nancy L. Pedersen, Anton Lager, Cecilia Magnusson, Maria Rosaria Galanti, Rino Bellocco, Byhamre, M, Araghi, M, Alfredsson, L, Bellocco, R, Engstrom, G, Eriksson, M, Galanti, M, Jansson, J, Lager, A, Lundberg, M, Ostergren, P, Pedersen, N, Trolle Lagerros, Y, Ye, W, Wennberg, P, and Magnusson, C

Subjects
Male, medicine.medical_specialty, Tobacco, Smokeless, Epidemiology, Swedish snu, moist oral snuff, Tobacco Use, 03 medical and health sciences, 0302 clinical medicine, cardiovascular mortality, Internal medicine, cancer mortality, Humans, Medicine, Cardiac and Cardiovascular Systems, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Proportional Hazards Models, Cardiovascular mortality, Sweden, Cancer Death Rate, Kardiologi, Health consequences, business.industry, Cancer, Public Health, Global Health, Social Medicine and Epidemiology, smokeless tobacco, General Medicine, All-cause mortality, medicine.disease, Swedish snus, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Pooled analysis, Smokeless tobacco, 030220 oncology & carcinogenesis, Snus, business
Abstract

Background The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborative pooling project. Methods We followed 169 103 never-smoking men from eight Swedish cohort studies, recruited in 1978–2010. Shared frailty models with random effects at the study level were used in order to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of mortality associated with snus use. Results Exclusive current snus users had an increased risk of all-cause mortality (aHR 1.28, 95% CI 1.20–1.35), cardiovascular mortality (aHR 1.27, 95% CI 1.15–1.41) and other cause mortality (aHR 1.37, 95% CI 1.24–1.52) compared with never-users of tobacco. The risk of cancer mortality was also increased (aHR 1.12, 95% CI 1.00–1.26). These mortality risks increased with duration of snus use, but not with weekly amount. Conclusions Snus use among men is associated with increased all-cause mortality, cardiovascular mortality, with death from other causes and possibly with increased cancer mortality.

Published
2020

11. Cotinine as a measure of smoking in observational studies of multiple sclerosis

Author

Anna Karin Hedström, Lars Alfredsson, and Tomas Olsson

Subjects
Nicotine, medicine.medical_specialty, Multiple Sclerosis, Disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Swedish population, Internal medicine, medicine, Humans, Cotinine, Secondary progressive, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Smoking, Case-control study, medicine.disease, Neurology, chemistry, Case-Control Studies, Observational study, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Studies using cotinine levels to define smokers have generally failed to detect an association between smoking and multiple sclerosis (MS). Using a Swedish population-based case-control study, we show that associations in relation to MS risk and progression differ considerably depending on how smoking is measured. The risk of conversion into secondary progressive disease was increased among smokers when self-reported smoking history, but not presumed cotinine levels, was used to define smokers. Defining smoking by cotinine levels without distinguishing between different sources of nicotine may lead to severely biased estimates of the association between smoking and both MS risk and progression.

Published
2020

12. Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

Author

Jessica Edstorp, Yuxia Wei, Emma Ahlqvist, Lars Alfredsson, Valdemar Grill, Leif Groop, Bahareh Rasouli, Elin P. Sørgjerd, Per M. Thorsby, Tiinamaija Tuomi, Bjørn O. Åsvold, Sofia Carlsson, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, University of Helsinki, HUS Abdominal Center, Tiinamaija Tuomi Research Group, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Medicine, and Endokrinologian yksikkö

Subjects
Tobacco, Smokeless, GENES, Genotype, Endocrinology, Diabetes and Metabolism, Risk Assessment, LADA, DISEASE, Tobacco, Internal Medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, INCREASED RISK, Røyking, Latent autoimmune diabetes in adults, Incidence, Smoking, ASSOCIATION, Mendelian Randomization Analysis, Lada, Gene-environment interaction, Tobacco use, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, ONSET, MENDELIAN RANDOMIZATION, Mendelian randomisation analysis, SNUS, Tobakk, Genome-Wide Association Study
Abstract

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract

Published
2022

13. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. 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F., Ehrlich, S., Escaramis, G., Espeseth, T., Estivill, X., Farmer, A., Favaro, A., Fischer, K., Floyd, J. A. B., Focker, M., Foretova, L., Forzan, M., Franklin, C. S., Gambaro, G., Giuranna, J., Giusti-Rodriquez, P., Gonidakis, F., Gordon, S., Mayora, M. G., Guillaume, S., Hanscombe, K. B., Hatzikotoulas, K., Hebebrand, J., Helder, S. G., Henders, A. K., Herpertz-Dahlmann, B., Herzog, W., Hinney, A., Horwood, L. J., Hubel, C., Petersen, L. V., Purves, K. L., Raevuori, A., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op 't Landt, M. C. T., Slopien, A., Soranzo, N., Sorbi, S., Southam, L., Steen, V. W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jordan, J., Julia, A., Kalsi, G., Kaminska, D., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, M. 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T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

14. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author

Saedis, Saevarsdottir, Lilja, Stefansdottir, Patrick, Sulem, Gudmar, Thorleifsson, Egil, Ferkingstad, Gudrun, Rutsdottir, Bente, Glintborg, Helga, Westerlind, Gerdur, Grondal, Isabella C, Loft, Signe Bek, Sorensen, Benedicte A, Lie, Mikael, Brink, Lisbeth, Ärlestig, Asgeir Orn, Arnthorsson, Eva, Baecklund, Karina, Banasik, Steffen, Bank, Lena I, Bjorkman, Torkell, Ellingsen, Christian, Erikstrup, Oleksandr, Frei, Inger, Gjertsson, Daniel F, Gudbjartsson, Sigurjon A, Gudjonsson, Gisli H, Halldorsson, Oliver, Hendricks, Jan, Hillert, Estrid, Hogdall, Søren, Jacobsen, Dorte Vendelbo, Jensen, Helgi, Jonsson, Alf, Kastbom, Ingrid, Kockum, Salome, Kristensen, Helga, Kristjansdottir, Margit H, Larsen, Asta, Linauskas, Ellen-Margrethe, Hauge, Anne G, Loft, Bjorn R, Ludviksson, Sigrun H, Lund, Thorsteinn, Markusson, Gisli, Masson, Pall, Melsted, Kristjan H S, Moore, Heidi, Munk, Kaspar R, Nielsen, Gudmundur L, Norddahl, Asmundur, Oddsson, Thorunn A, Olafsdottir, Pall I, Olason, Tomas, Olsson, Sisse Rye, Ostrowski, Kim, Hørslev-Petersen, Solvi, Rognvaldsson, Helga, Sanner, Gilad N, Silberberg, Hreinn, Stefansson, Erik, Sørensen, Inge J, Sørensen, Carl, Turesson, Thomas, Bergman, Lars, Alfredsson, Tore K, Kvien, Søren, Brunak, Kristján, Steinsson, Vibeke, Andersen, Ole A, Andreassen, Solbritt, Rantapää-Dahlqvist, Merete Lund, Hetland, Lars, Klareskog, Johan, Askling, Leonid, Padyukov, Ole Bv, Pedersen, Unnur, Thorsteinsdottir, Ingileif, Jonsdottir, and Kari, Stefansson

Subjects
Proteomics, rheumatoid arthritis, autoantibodies, Janus Kinases/genetics, Immunology, polymorphism, genetic, General Biochemistry, Genetics and Molecular Biology, polymorphism, Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics, Arthritis, Rheumatoid, Rheumatology, genetic, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Medicinsk genetik, Rheumatology and Autoimmunity, Janus Kinases, Reumatologi och inflammation, Genetic Predisposition to Disease/genetics, Biochemistry and Molecular Biology, Interferon-alpha, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Arthritis, Rheumatoid/genetics, STAT Transcription Factors/genetics, STAT Transcription Factors, Signal Transduction/genetics, Medical Genetics, Biokemi och molekylärbiologi, Genome-Wide Association Study, Signal Transduction
Abstract

Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen

Published
2022

15. The population genomic legacy of the second plague pandemic

Author

Shyam Gopalakrishnan, S. Sunna Ebenesersdóttir, Inge K.C. Lundstrøm, Gordon Turner-Walker, Kristjan H.S. Moore, Pierre Luisi, Ashot Margaryan, Michael D. Martin, Martin Rene Ellegaard, Ólafur þ. Magnússon, Ásgeir Sigurðsson, Steinunn Snorradóttir, Droplaug N. Magnúsdóttir, Jason E. Laffoon, Lucy van Dorp, Xiaodong Liu, Ida Moltke, María C. Ávila-Arcos, Joshua G. Schraiber, Simon Rasmussen, David Juan, Pere Gelabert, Toni de-Dios, Anna K. Fotakis, Miren Iraeta-Orbegozo, Åshild J. Vågene, Sean Dexter Denham, Axel Christophersen, Hans K. Stenøien, Filipe G. Vieira, Shanlin Liu, Torsten Günther, Toomas Kivisild, Ole Georg Moseng, Birgitte Skar, Christina Cheung, Marcela Sandoval-Velasco, Nathan Wales, Hannes Schroeder, Paula F. Campos, Valdís B. Guðmundsdóttir, Thomas Sicheritz-Ponten, Bent Petersen, Jostein Halgunset, Edmund Gilbert, Gianpiero L. Cavalleri, Eivind Hovig, Ingrid Kockum, Tomas Olsson, Lars Alfredsson, Thomas F. Hansen, Thomas Werge, Eske Willerslev, Francois Balloux, Tomas Marques-Bonet, Carles Lalueza-Fox, Rasmus Nielsen, Kári Stefánsson, Agnar Helgason, M. Thomas P. Gilbert, Carlsberg Foundation, Danish National Research Foundation, Lundbeck Foundation, European Research Council, Research Council of Norway, Science Foundation Ireland, Analytical, Environmental & Geo-Chemistry, and Chemistry

Subjects
pandemic genomics, Plague, population genomics, Yersinia pestis, Pandemic genomics, selection, second plague pandemic, General Biochemistry, Genetics and Molecular Biology, plague, Population replacement, Second plague pandemic, Medisinske Fag: 700 [VDP], Genetics, Trondheim, Humans, population replacement, Metagenomics, Matematikk og Naturvitenskap: 400 [VDP], Genetik, General Agricultural and Biological Sciences, Population genomics, Pandemics, Selection, Genome, Bacterial, Phylogeny
Abstract

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics., We acknowledge the following for funding our research: Carlsbergfondet grants CF14-0995 and Marie Skłodowska-Curie Actions grant 655732 (to S.G.), Danish National Research Foundation grant DNRF94, Lundbeckfonden grant R52-5062, Carlsbergfondet grant CF18-1109 and ERC Consolidator grant (681396-ExtinctionGenomics) (to M.T.P.G.), and MEDHEAL600 funded by the Research Council of Norway (FRIHUMSAM) project number is 262424. G.L.C. is supported by the Science Foundation Ireland under grant number 16/RC/3948. T.M.B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 864203).

Published
2022

16. Stressful life events are associated with the risk of multiple sclerosis

Author

Lars Alfredsson, Jan Hillert, Xia Jiang, Tomas Olsson, and Ingrid Kockum

Subjects
Male, medicine.medical_specialty, Multiple Sclerosis, Population, Disease, negative events, Logistic regression, Affect (psychology), association study, 03 medical and health sciences, stress, 0302 clinical medicine, Risk Factors, Internal medicine, Surveys and Questionnaires, Epidemiology, Medicine, Humans, sex disparity, 030212 general & internal medicine, Adverse effect, education, Life Style, risk, education.field_of_study, business.industry, Multiple sclerosis, Confounding, medicine.disease, Neurology, Case-Control Studies, Original Article, epidemiology, Female, Neurology (clinical), major life changes, business, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

BACKGROUND AND PURPOSE Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population-based case-control study on this topic. METHODS Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time. RESULTS Compelling evidence was found for a link between major life events and risk of MS - most events significantly increased disease risk by 17%-30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development. CONCLUSION Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS.

Published
2020

17. Presence of autoantibodies in 'seronegative' rheumatoid arthritis associates with classical risk factors and high disease activity

Author

Evan Reed, Boel Brynedal, Linda Mathsson-Alm, Johan Rönnelid, Monika Hansson, Guy Serre, Per-Johan Jakobsson, Rikard Holmdahl, Saedis Saevarsdottir, Martin Cornillet, Karl Skriner, Karin Lundberg, Lars Alfredsson, Anna Karin Hedström, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Karolinska University Hospital [Stockholm], Thermo Fisher Scientific, Uppsala Universitet [Uppsala], Karolinska Institutet [Stockholm], University of Iceland [Reykjavik], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], and PINIER, CHRISTINE

Subjects
musculoskeletal diseases, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Disease, Peptides, Cyclic, Anti-Citrullinated Protein Antibodies, Disease activity, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatoid Factor, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, HLA-DRB1 shared epitope (SE), Medicine, Rheumatoid factor, Humans, Rheumatoid arthritis, skin and connective tissue diseases, Seronegative rheumatoid arthritis, Rheumatology and Autoimmunity, Autoantibodies, 030203 arthritis & rheumatology, Reumatologi och inflammation, biology, business.industry, Smoking, Autoantibody, Cyclic citrullinated peptide (CCP), Rheumatoid factor (RF), medicine.disease, Rheumatology, 3. Good health, Disease activity score for 28 joints (DAS28), Rheumatoid arthritis (RA), Anti-citrullinated protein antibodies (ACPA), Immunology, biology.protein, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anti-carbamylated protein antibodies (anti-CarP), Antibody, Iktsýki, lcsh:RC925-935, business, 030215 immunology, Research Article
Abstract

Publisher's version (útgefin grein), Background: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative"RA, associated with worse clinical outcome. Conclusions: "Seronegative"RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2-/IgM RF- patients with a high need for active treatment., This work was supported by grants from the Swedish Research Council (2017-01696); King Gustav V:s 80-year foundation (FAI-2016-0273); the EU funded consortia TRIGGER (FP7-Health-2013-306029); and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BeTheCure (grant n° 115142), and RTCure (grant n° 777357). Open access funding provided by Karolinska Institute.

Published
2020

18. Higher body mass index at ages 16 to 20 years is associated with increased risk of a multiple sclerosis diagnosis in subsequent adulthood among men

Author

Yin Xu, Judith S. Brand, Scott Montgomery, Shahram Bahmanyar, Lars Alfredsson, Kelsi A Smith, Ayako Hiyoshi, and Tomas Olsson

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Multiple Sclerosis, Neurology, Adolescent, Body Mass Index, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, 0502 economics and business, medicine, Humans, Obesity, business.industry, Multiple sclerosis, 05 social sciences, Overweight, medicine.disease, Increased risk, Physical Fitness, 050211 marketing, Neurology (clinical), Underweight, medicine.symptom, business, Body mass index, 030217 neurology & neurosurgery
Abstract

Background: Evidence for the association between body mass index (BMI) and multiple sclerosis (MS) among men remains mixed. Objective and methods: Swedish military conscription and other registers identified MS after age of 20 years and BMI at ages 16–20 years ( N = 744,548). Results: Each unit (kg/m2) BMI increase was associated with greater MS risk (hazard ratio and 95% confidence interval = 1.034, 1.016–1.053), independent of physical fitness (1.021, 1.001–1.042). Categorised, overweight and obesity were associated with statistically significant raised MS risk compared to normal weight, but not after adjustment for physical fitness. Conclusion: MS risk rises with increasing BMI, across the entire BMI range.

Published
2020

19. Modifiable environmental exposure and risk of rheumatoid arthritis—current evidence from genetic studies

Author

Lars Alfredsson and Xia Jiang

Subjects
medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Genome-wide association study, Review, Bioinformatics, Arthritis, Rheumatoid, Mendelian randomization, Epidemiology, Medicine, Humans, Obesity, Rheumatoid arthritis, Genetic instruments, business.industry, Confounding, Instrumental variable, Modifiable environmental exposures, Environmental exposure, Environmental Exposure, Mendelian Randomization Analysis, Causality, Causal inference, Observational study, lcsh:RC925-935, business
Abstract

Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology. It has been shown that genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors. Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality. Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data. The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design. In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis. We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions. The application of MR design in the field of rheumatology remains limited. Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found. Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results. Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers). As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered. Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates. To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.

Published
2020

20. A Gene–Environment Interaction Between Smoking and Gene polymorphisms Provides a High Risk of Two Subgroups of Sarcoidosis

Author

Lina-Marcela Diaz-Gallo, Tomoko Iseda, Lars Alfredsson, Susanna Kullberg, Camilla Bengtsson, Leonid Padyukov, Karina Patasova, Ingrid Kockum, Natalia V. Rivera, Johan Grunewald, and Anders Eklund

Subjects
0301 basic medicine, False discovery rate, Oncology, Adult, Male, medicine.medical_specialty, Genotype, Sarcoidosis, Hla genes, lcsh:Medicine, Disease, Logistic regression, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, lcsh:Science, Gene, Sweden, Multidisciplinary, Polymorphism, Genetic, business.industry, Disease genetics, Smoking, lcsh:R, Membrane Proteins, Receptors, Interleukin, Middle Aged, Translational research, medicine.disease, 030104 developmental biology, Phenotype, 030228 respiratory system, Female, Gene-Environment Interaction, lcsh:Q, business
Abstract

The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren’s syndrome (LS) and patients without Löfgren’s syndrome (non-LS). To quantify smoking effects in sarcoidosis, we performed a gene-environment interaction study in a Swedish population-based case-control study consisting of 3,713 individuals. Cases and controls were classified according to their cigarette smoking status and genotypes by Immunochip platform. Gene-smoking interactions were quantified by an additive interaction model using a logistic regression adjusted by sex, age and first two principal components. The estimated attributable proportion (AP) was used to quantify the interaction effect. Assessment of smoking effects with inclusion of genetic information revealed 53 (in LS) and 34 (in non-LS) SNP-smoking additive interactions at false discovery rate (FDR) below 5%. The lead signals interacting with smoking were rs12132140 (AP = 0.56, 95% CI = 0.22–0.90), p = 1.28e-03) in FCRL1 for LS and rs61780312 (AP = 0.62, 95% CI = 0.28–0.90), p = 3e-04) in IL23R for non-LS. We further identified 16 genomic loci (in LS) and 13 (in non-LS) that interact with cigarette smoking. These findings suggest that sarcoidosis risk is modulated by smoking due to genetic susceptibility. Therefore, patients having certain gene variants, are at a higher risk for the disease. Consideration of individual’s genetic predisposition is crucial to quantify effects of smoking in sarcoidosis.

Published
2019

21. Investigation of the association between coffee and risk of RA-results from the Swedish EIRA study

Author

Helga Westerlind, Justine Dukuzimana, Xiaomin Lu, Lars Alfredsson, Lars Klareskog, and Daniela Di Giuseppe

Subjects
Arthritis, Rheumatoid, Male, Sweden, Risk Factors, Case-Control Studies, Humans, Female, Middle Aged, Coffee
Abstract

Background Studies on the association between coffee, a modifiable lifestyle factor, and rheumatoid arthritis (RA), a chronic autoimmune disease primarily affecting the joints, have been conflicting. The aim of the present study was to study the association between coffee consumption and risk of RA in the context of different lifestyle factors. Methods We included 2184 cases (72% women, mean age 55 years) newly diagnosed with RA during 2005–2018 in Sweden and 4201 controls matched on age, sex, and residential area. Data on coffee consumption was collected through a food frequency questionnaire and categorized into < 2 (reference), 2–< 4, 4–< 6, and ≥ 6 cups/day. We calculated odds ratios (OR) with 95% confidence intervals (CI) for coffee consumption and risk of RA, in a crude model (taking matching factors into account), and then adjusted first for smoking and further for BMI, educational level, alcohol consumption, and physical activity. We also stratified analyses on sex, smoking, rheumatoid factor, and anti-CCP2 status. Results In the crude model, high coffee consumption was associated with increased risk of RA (OR = 1.50, 95% CI 1.20–1.88 for ≥ 6 cups/day compared to < 2 cups). After adjusting for smoking, the OR decreased and was no longer statistically significant (OR = 1.16, 95% CI 0.92–1.46) and decreased further in the full model (OR = 1.14 95% CI 0.89–1.45). This pattern held true in all strata. Conclusion The findings from this large, population-based case-control study did not support a significant association between coffee consumption and risk of RA as a whole nor within different subgroups.

Published
2021

22. Smoking Attributable Risk in Multiple Sclerosis

Author

Ali Manouchehrinia, Jesse Huang, Jan Hillert, Lars Alfredsson, Tomas Olsson, Ingrid Kockum, and Cris S. Constantinescu

Subjects
Male, Multiple Sclerosis, Risk Factors, Case-Control Studies, Immunology, Smoking, Tobacco Smoking, Immunology and Allergy, Humans, Female
Abstract

Tobacco smoke is an important modifiable environmental risk factor for multiple sclerosis (MS) risk. The population attributable fraction (AF) of MS due to smoking can be used to assess the contribution of smoking to the risk of MS development. We conducted a matched case-control study, including individuals with MS and population-based controls. Overall, sex- and genetic risk score-stratified AF due to smoking were calculated by fitting logistic regression models. We included 9,419 individuals with MS and 9,419 population-based matched controls. At the time of MS onset 44.1% of persons with MS and 35.9% of controls ever regularly smoked of which 38.1% and 29.2% were still smoking. The overall AF was 13.1% (95%CI: 10.7 to 15.4). The AF was 10.6% (95%CI: 7.4 to 13.7) in females and 19.1% (95%CI: 13.1 to 25.1) in males. The AF was 0.6% (95%CI: 0.0 to 2) in ex-smokers. In those having human leucocyte antigen (HLA) and non-HLA risk scores above the median levels of controls, the AF was 11.4% (95%CI: 6.8 to 15.9) and 12% (95%CI: 7.7 to 16.3), respectively. The AF was 17.6% (95%CI: 10.2 to 24.9) and 18.6% (95%CI: 5.5 to 31.6) in those with HLA and non-HLA risk scores below the median levels in controls, respectively. We noticed a decline in AF in recent birth cohorts. This study indicates that at least 13% of cases of MS could be prevented through the avoidance of tobacco smoking. Considering the prevalence of MS, this represents a very large group of people in absolute number.

Published
2021

23. Antibodies to a Citrullinated

Author

Natalia, Sherina, Charlotte, de Vries, Nastya, Kharlamova, Natalie, Sippl, Xia, Jiang, Boel, Brynedal, Elin, Kindstedt, Monika, Hansson, Linda, Mathsson-Alm, Lena, Israelsson, Ragnhild, Stålesen, Saedis, Saevarsdottir, Rikard, Holmdahl, Aase, Hensvold, Gunnar, Johannsen, Kaja, Eriksson, Federica, Sallusto, Anca I, Catrina, Johan, Rönnelid, Caroline, Grönwall, Tülay, Yucel-Lindberg, Lars, Alfredsson, Lars, Klareskog, Luca, Piccoli, Vivianne, Malmström, Khaled, Amara, and Karin, Lundberg

Subjects
Arthritis, Rheumatoid, Epitopes, Immunoglobulin G, Antibodies, Monoclonal, Citrulline, Humans, Peptides, Porphyromonas gingivalis, Autoantibodies
Abstract

Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium

Published
2021

24. Allergic conditions and risk of rheumatoid arthritis: a Swedish case-control study

Author

Vanessa L, Kronzer, Helga, Westerlind, Lars, Alfredsson, Cynthia S, Crowson, Lars, Klareskog, Marie, Holmqvist, and Johan, Askling

Subjects
Arthritis, Rheumatoid, Sweden, Risk Factors, Case-Control Studies, Hypersensitivity, Humans
Abstract

To determine the association of allergic conditions with incident rheumatoid arthritis (RA), especially in relation to smoking history and anti-citrullinated peptide antibody (ACPA) status.This case-control study included 3515 incident RA cases and 5429 matched controls from the Epidemiological Investigation of Rheumatoid Arthritis study 1995 to 2016, including questionnaire-based information on eight allergic conditions composed from a list of 59 unique allergies. We used logistic regression and adjusted ORs (aOR) to assess the association between allergic conditions and risk of RA, adjusting for age, sex, residential area, body mass index, education, and smoking, and stratified by smoking and ACPA.A history of any reported allergy was equally common in RA (n=1047, 30%) as among population controls (n=1540, 29%), aOR 1.04, 95% CI 0.95 to 1.15. Metal, respiratory, food, plant/pollen and chemical allergies were not associated with risk of RA. By contrast, statistically significant associations were observed for animal dander allergy (6% vs 5%, aOR 1.37, 95% CI 1.03 to 1.82), especially in ACPA-positive RA (aOR 1.46 95% CI 1.06 to 2.01) and for atopic dermatitis, in particular for older and ACPA-negative RA (aOR 2.33, 95% CI 1.37 to 3.96 at age 80). Never smokers with allergic rhinitis also had increased risk of developing RA (aOR 1.30, 95% CI 1.00 to 1.68).Most common allergies do not increase risk of RA, nor do they protect against RA. However, some allergic conditions, notably animal dander allergy, atopic dermatitis and allergic rhinitis, were associated with an increased risk for RA.

Published
2021

25. The increased risk of multiple sclerosis associated with HLA-DRB1*15:01 and smoking is modified by alcohol consumption

Author

Tomas Olsson, Lars Alfredsson, and Anna Karin Hedström

Subjects
Adult, Male, medicine.medical_specialty, Inverse Association, Multiple Sclerosis, Adolescent, Alcohol Drinking, Science, Logistic regression, Article, Internal medicine, Medicine, Humans, HLA-DRB1, Aged, Multidisciplinary, business.industry, Multiple sclerosis, Smoking, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Increased risk, Neurology, Risk factors, Female, business, Alcohol consumption, HLA-DRB1 Chains
Abstract

Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case–control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend

Published
2021

26. A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis

Author

Zelmina Lubovac-Pilav, Lars Alfredsson, Tejaswi V. S. Badam, Hendrik Arnold de Weerd, Mika Gustafsson, Ingrid Kockum, Maja Jagodic, Tomas Olsson, and David Martínez-Enguita

Subjects
Epigenomics, Computer science, Network modules, Genome-wide association study, Disease, QH426-470, Benchmark, computer.software_genre, Methylomics, 0302 clinical medicine, Gene Regulatory Networks, Multi-omics, 0303 health sciences, 3. Good health, Identification (information), Benchmark (computing), Data integration, Network analysis, DNA microarray, Medical Genetics, Research Article, Biotechnology, Multiple sclerosis, Risk factors, Disease modules, Protein network analysis, Transcriptomics, Genome-wide association analysis, Multiple Sclerosis, Bioinformatik och systembiologi, Computational biology, Biology, 03 medical and health sciences, Genetics, Humans, Relevance (information retrieval), Epigenetics, Medicinsk genetik, 030304 developmental biology, Bioinformatics and Systems Biology, Immunology in the medical area, Omics, Workflow, Immunologi inom det medicinska området, computer, TP248.13-248.65, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background: There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules. Result: We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10− 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS. Conclusions: We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases. CC BY 4.0© 2021, The Author(s)This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.Correspondence: mika.gustafsson@liu.seThis work was supported by the Swedish Research Council (grant 2015–03807(M.G.), grant 2018–02638(M.J.)), the Swedish foundation for strategic research (grant SB16–0095(M.G.)), the Center for Industrial IT (CENIIT)(M.G.), European Union Horizon 2020/European Research Council Consolidator grant (Epi4MS, grant 818170(M.J.)), Knut and Alice Wallenberg Foundation (grant 2019.0089(M.J.)) and the Knowledge Foundation (grant 20170298(Z.L.)). Computational resources were granted by Swedish National Infrastructure for Computing (SNIC; SNIC 2020/5–177, LiU-2018-12 and LiU-2019-25). The funding bodies had no role in the study and collection, ana-lysis, and interpretation of data and in writing the manuscript. Open Accessfunding provided by Linköping University.

Published
2021

27. Is tea consumption associated with reduction of risk of rheumatoid arthritis? A Swedish case-control study

Author

Helga Westerlind, Daniela Di Giuseppe, Lars Klareskog, Ida Palmqvist, Lars Alfredsson, and Saedis Saevarsdottir

Subjects
Risk, Diseases of the musculoskeletal system, Arthritis, Rheumatoid, Risk Factors, Statistical significance, Humans, Medicine, Tea consumption, Rheumatoid arthritis, Sweden, Consumption (economics), Tea, business.industry, Smoking, Case-control study, Odds ratio, ACPA, medicine.disease, Confidence interval, Diet, RC925-935, Case-Control Studies, business, Body mass index, Research Article, Demography
Abstract

BackgroundTea is a popular beverage around the world and has properties that can affect the immune system. The association between tea consumption and the risk of rheumatoid arthritis (RA), a chronic autoimmune disease primarily affecting the joints, is not well studied and results are conflicting.MethodsWe collected data on tea consumption for 2237 incident RA cases diagnosed 2005–2018 and 4661 controls matched on age, sex, and residential area. Tea consumption was classified into no (0 cups/day), irregular (ResultsAmong the cases, we found 57.3% to be ever consumers of tea with 19.7 having a high tea consumption. Corresponding figures for the controls were 58.4% ever drinkers with 22.1% high tea consumers. High tea consumption had an inverse association to the risk of RA compared to irregular consumption [OR = 0.78 (95% CI 0.66–0.92)], but the association lost statistical significance in the adjusted model [adjusted OR (adjOR) = 0.85 (95% CI 0.71–1.01)]. Among non-tea consumers, a protective effect was also observed compared to irregular consumers [adjOR = 0.82 (95% CI 0.70–0.88)], but this association did not withstand sensitivity analysis, possibly due to bias. In the ACPA-positive group and among current smokers, a protective effect of tea consumption was observed among the high tea consumers [adjOR = 0.76 (95% CI 0.62–0.94) and adjOR = 0.60 (95% CI 0.38–0.95), respectively].ConclusionsThis study suggests a protective effect of high consumption of tea, among smokers and for ACPA-positive RA.Trial registrationNot applicable

Published
2021

28. Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology

Author

Lars Alfredsson, Anna Karin Hedström, Jesse Huang, Nicole Brenner, Tomas Olsson, Tim Waterboer, Ingrid Kockum, and Julia Butt

Subjects
education.field_of_study, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Multiple Sclerosis, business.industry, Multiple sclerosis, Population, Case-control study, Odds ratio, Human leukocyte antigen, medicine.disease, Antibodies, Viral, Neurology, Antigen, Epstein-Barr Virus Nuclear Antigens, Case-Control Studies, Immunology, Vitamin D and neurology, medicine, Sunlight, Humans, Neurology (clinical), education, business, Epstein–Barr virus infection
Abstract

BACKGROUND Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk. METHODS We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). RESULTS Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01 status. CONCLUSIONS Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

Published
2021

29. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Author

Mark Caulfield, Solbritt Rantapää Dahlqvist, Eleftheria Zeggini, Michael Weedon, Paul Martin, Elaine Dennison, Patricia Munroe, Detelina Grozeva, John Isaacs, Stephen Eyre, Alex MacGregor, Kate Duffus, Andrew Hattersley, DOROTHEE DIOGO, Luis Rodriguez-Rodriguez, Steven Young-Min, Chris Wallace, Miguel Gonzalez-Gay, Tom Huizinga, Stephen Newhouse, Alexandra Zhernakova, Melanie Newport, Deborah Symmons, Lisa Jones, Michael O'Donovan, Wan-Fai Ng, Nadira Yusupovna Yuldasheva, Cyrus Cooper, Willem Ouwehand, Philip Conaghan, Gerome Breen, Lars Alfredsson, Karim Raza, Hana Lango Allen, Jane Worthington, Mark Iles, Ann Morgan, Professor David Dunger, Soumya Raychaudhuri, Panos Deloukas, Marwan Bukhari, Alastair Forbes, Allan Young, Lars Klareskog, Leonid Padyukov, Fraser Birrell, Charlie Lees, Anne Barton, Martin Tobin, Patrick Concannon, Jon Packham, Natalie Prescott, Javier Martin, Kimme Hyrich, Lude Franke, John Bowes, Ian Bruce, Chiea Chuen Khor, Stephen Rich, Miles Parkes, Sarah Hunt, Tim Bishop, Gosia Trynka, Richard Dobson, Anna Dominiczak, Cisca Wijmenga, Mark McCarthy, Cecilia Lindgren, Rene Toes, Alistair Hall, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Bowes, John [0000-0003-4659-031X], Zhernakova, Alexandra [0000-0002-4574-0841], Padyukov, Leonid [0000-0003-2950-5670], Toes, Rene EM [0000-0002-9618-6414], Wijmenga, Cisca [0000-0002-5635-1614], Trynka, Gosia [0000-0002-6955-9529], Franke, Lude [0000-0002-5159-8802], Alfredsson, Lars [0000-0003-1688-6697], Khor, Chiea Chuen [0000-0002-1128-4729], Concannon, Pat [0000-0002-5801-1859], Onengut-Gumuscu, Suna [0000-0002-6563-8334], Rodriguez-Rodriguez, Luis [0000-0002-2869-7861], Rantapää-Dahlqvist, Solbritt [0000-0001-8259-3863], Raychaudhuri, Soumya [0000-0002-1901-8265], Klareskog, Lars [0000-0001-9601-6186], and Apollo - University of Cambridge Repository

Subjects
EXPRESSION, Male, Arthritis, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Polymorphism (computer science), Genetics, medicine, SNP, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, Genotyping, METAANALYSIS, 030304 developmental biology, Genetic association, Autoantibodies, Oligonucleotide Array Sequence Analysis, 030203 arthritis & rheumatology, 0303 health sciences, Chromosome Mapping, ASSOCIATION, medicine.disease, RISK LOCI, INTERLEUKIN-6 RECEPTOR, Genetic Loci, Female, SNP array, Genome-Wide Association Study
Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

Published
2021
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30. Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis

Author

Eleftheria Theodoropoulou, Maja Jagodic, Francesco Marabita, Fredrik Piehl, and Lars Alfredsson

Subjects
Adult, Male, Aging, Cancer Research, Multiple Sclerosis, Adolescent, Biology, Epigenesis, Genetic, Blood cell, Young Adult, Sex Factors, Genetics, medicine, Humans, Epigenetics, Gene expression omnibus, Multiple sclerosis, DNA Methylation, Middle Aged, medicine.disease, Phenotype, Pathophysiology, medicine.anatomical_structure, Case-Control Studies, DNA methylation, Female, Sorted Cells
Abstract

Aim: Accumulating evidence links epigenetic age to diseases and age-related conditions, but little is known about its association with multiple sclerosis (MS). Materials & methods: We estimated epigenetic age acceleration measures using DNA methylation from blood or sorted cells of MS patients and controls. Results: In blood, sex (p = 4.39E-05) and MS (p = 2.99E-03) explained the variation in age acceleration, and isolated blood cell types showed different epigenetic age. Intrinsic epigenetic age acceleration and extrinsic epigenetic age acceleration were only associated with sex (p = 2.52E-03 and p = 1.58E-04, respectively), while PhenoAge Acceleration displayed positive association with MS (p = 3.40E-02). Conclusion: Different age acceleration measures are distinctly influenced by phenotypic factors, and they might measure separate pathophysiological aspects of MS. Data deposition: DNA methylation data can be accessed at Gene Expression Omnibus database under accession number GSE35069, GSE43976, GSE106648, GSE130029, GSE130030.

Published
2019

31. Machine-learning–based knowledge discovery in rheumatoid arthritis–related registry data to identify predictors of persistent pain

Author

Jörn Lötsch, Jon Lampa, and Lars Alfredsson

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, MEDLINE, Pain, Arthritis, Arthritis, Rheumatoid, Machine Learning, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Knowledge extraction, Risk Factors, 030202 anesthesiology, Epidemiology, Humans, Medicine, Registries, Young adult, Aged, Sweden, business.industry, Middle Aged, Knowledge Discovery, medicine.disease, Random forest, Anesthesiology and Pain Medicine, Neurology, Categorization, Rheumatoid arthritis, Physical therapy, Female, Neurology (clinical), business, Algorithms, 030217 neurology & neurosurgery
Abstract

Early detection of patients with chronic diseases at risk of developing persistent pain is clinically desirable for timely initiation of multimodal therapies. Quality follow-up registries may provide the necessary clinical data; however, their design is not focused on a specific research aim, which poses challenges on the data analysis strategy. Here, machine-learning was used to identify early parameters that provide information about a future development of persistent pain in rheumatoid arthritis (RA). Data of 288 patients were queried from a registry based on the Swedish Epidemiological Investigation of RA. Unsupervised data analyses identified the following 3 distinct patient subgroups: low-, median-, and high-persistent pain intensity. Next, supervised machine-learning, implemented as random forests followed by computed ABC analysis-based item categorization, was used to select predictive parameters among 21 different demographic, patient-rated, and objective clinical factors. The selected parameters were used to train machine-learned algorithms to assign patients pain-related subgroups (1000 random resamplings, 2/3 training, and 1/3 test data). Algorithms trained with 3-month data of the patient global assessment and health assessment questionnaire provided pain group assignment at a balanced accuracy of 70%. When restricting the predictors to objective clinical parameters of disease severity, swollen joint count and tender joint count acquired at 3 months provided a balanced accuracy of RA of 59%. Results indicate that machine-learning is suited to extract knowledge from data queried from pain- and disease-related registries. Early functional parameters of RA are informative for the development and degree of persistent pain.

Published
2019

32. IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis

Author

Hannes Lindahl, M Lindén, Karolina Tandre, Sahl Khalid Bedri, Mohsen Khademi, Lars Alfredsson, Colin P. Glover, André Ortlieb Guerreiro-Cacais, Maja Jagodic, Mathias Linnerbauer, Ingrid Kockum, Lars Rönnblom, Tomas Olsson, Lorraine Irving, Clare A. Jones, Nada Abdelmagid, and Claire Hollins

Subjects
Candidate gene, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Genotype, T-Lymphocytes, medicine.medical_treatment, Immunology, Biology, Lymphocyte Activation, Polymorphism, Single Nucleotide, Interleukin 22, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Receptor, Multiple sclerosis, Binding protein, Receptors, Interleukin, medicine.disease, In vitro, Rats, Cytokine, Cancer research, 030215 immunology
Abstract

Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22–mediated inhibition of T cell–derived IFN-γ expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS.

Published
2019

33. Environmental and genetic risk factors for MS: an integrated review

Author

Emmanuelle Waubant, Tomas Olsson, Robyn M. Lucas, Lars Alfredsson, Annette Langer-Gould, Ellen M. Mowry, and Jennifer Graves

Subjects
0301 basic medicine, Multiple Sclerosis, Neurosciences. Biological psychiatry. Neuropsychiatry, Review Article, Disease, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Immune homeostasis, Genetic risk, Gene–environment interaction, RC346-429, Review Articles, business.industry, General Neuroscience, Multiple sclerosis, Smoking, Environmental Exposure, medicine.disease, 3. Good health, Clinical Practice, 030104 developmental biology, Gene-Environment Interaction, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery, RC321-571
Abstract

Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

Published
2019

34. Genotypes of HLA, TCF7L2, and FTO as potential modifiers of the association between sweetened beverage consumption and risk of LADA and type 2 diabetes

Author

Tomas Andersson, Tiinamaija Tuomi, Lars Alfredsson, Alicja Wolk, Mozhgan Dorkhan, Leif Groop, Sofia Carlsson, Emma Ahlqvist, and Josefin E. Löfvenborg

Subjects
Male, 0301 basic medicine, Mediation (statistics), medicine.medical_specialty, endocrine system diseases, Genotype, Population, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Medicine (miscellaneous), 030209 endocrinology & metabolism, Type 2 diabetes, Body Mass Index, Autoimmune diabetes, BMI, 03 medical and health sciences, Sweetened beverage, 0302 clinical medicine, Insulin resistance, HLA Antigens, Internal medicine, Diabetes mellitus, Genetic predisposition, Humans, Medicine, T2D, education, Sugar-Sweetened Beverages, Sweden, Latent autoimmune diabetes in adults, education.field_of_study, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, Incidence, nutritional and metabolic diseases, Original Contribution, Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, Case-Control Studies, Female, medicine.symptom, business, Transcription Factor 7-Like 2 Protein, TCF7L2, Weight gain
Abstract

Purpose Sweetened beverage consumption is associated with type 2 diabetes (T2D) and LADA. We investigated to what extent this association is mediated by BMI and whether it is modified by genotypes of HLA, TCF7L2 rs7903146, or FTO rs9939609. Methods Swedish case–control data including incident cases of LADA (n = 386) and T2D (n = 1253) with matched population-based controls (n = 1545) was used. We estimated adjusted ORs of diabetes (95% CI) in relation to sweetened beverage intake (per daily 200 mL serving) and genotypes. The impact of BMI was estimated using causal mediation methodology. Associations with HOMA-IR and HOMA-B were explored through linear regression. Results Sweetened beverage intake was associated with increased risk of LADA (OR 1.15, 95% CI 1.03–1.29) and T2D (OR 1.21, 1.11–1.32). BMI was estimated to mediate 17% (LADA) and 56% (T2D) of the total risk. LADA was associated with risk variants of HLA (3.44, 2.63–4.50) and TCF7L2 (1.27, 1.00–1.61) but not FTO. Only among non-carriers of high-risk HLA genotypes was sweetened beverage intake associated with risk of LADA (OR 1.32, 1.06–1.56) and HOMA-IR (beta = 0.162, p = 0.0047). T2D was associated with TCF7L2 and FTO but not HLA, and the risk conferred by sweetened beverages appeared modified by FTO (OR 1.45, 95% CI 1.21–1.73 in non-carriers). Conclusions Our findings suggest that sweetened beverages are associated with LADA and T2D partly through mediation by excess weight, but possibly also through other mechanisms including adverse effects on insulin sensitivity. These effects seem more pronounced in individuals without genetic susceptibility.

Published
2019

35. Consumption of red meat, genetic susceptibility, and risk of LADA and type 2 diabetes

Author

Alicja Wolk, Tiinamaija Tuomi, Emma Ahlqvist, Leif Groop, Lars Alfredsson, Tomas Andersson, Josefin E. Löfvenborg, Sofia Carlsson, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, University Management, and Helsinki University Hospital Area

Subjects
Male, endocrine system diseases, Medicine (miscellaneous), CHILDREN, Type 2 diabetes, MELLITUS, 0302 clinical medicine, Medicine, 030212 general & internal medicine, Food science, Family history, education.field_of_study, Nutrition and Dietetics, HLA-CONFERRED SUSCEPTIBILITY, Original Contribution, ASSOCIATION, HLA, PREGNANCY, Red Meat Consumption, Red meat, Female, FATTY-ACIDS, SMOKING, Adult, Meat, Interaction, Population, 030209 endocrinology & metabolism, 03 medical and health sciences, Diabetes mellitus, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, ISLET AUTOIMMUNITY, Sweden, Latent autoimmune diabetes in adults, business.industry, nutritional and metabolic diseases, medicine.disease, Red meat intake, Diet, TCF7L2, Red Meat, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, BETA-CELL AUTOIMMUNITY, FOOD-CONSUMPTION, business
Abstract

Purpose Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. Methods Analyses were based on Swedish case–control data comprising incident cases of LADA (n = 465) and T2D (n = 1528) with matched, population-based controls (n = 1789; n = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. Results Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07–1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA-DQB1 and -DRB1 genotypes yielded OR 8.05 (95% CI 4.86–13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32–0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. Conclusion Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.

Published
2021

36. Widespread non-joint pain in early rheumatoid arthritis

Author

Lena Israelsson, Jon Lampa, Eva Skillgate, J. Lindqvist, E. Englid, Helga Westerlind, Lars Alfredsson, Maria E. C. Schelin, and Lars Klareskog

Subjects
musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Health Status, Immunology, MEDLINE, Comorbidity, Arthritis, Rheumatoid, Rheumatology, Internal medicine, medicine, Immunology and Allergy, Humans, Aged, Sweden, business.industry, Incidence, General Medicine, Early rheumatoid arthritis, Middle Aged, Joint pain, Cohort, Quality of Life, Female, medicine.symptom, Chronic Pain, business
Abstract

Objective: The aim of the study was to assess the development of widespread non-joint pain (WNP) in a cohort of patients with early rheumatoid arthritis (RA), the associated health-related quality ...

Published
2021

37. Social stressors and risk of rheumatoid arthritis and their relationship to known modifiable risk factors: results from the Swedish EIRA study

Author

L. Klareskog, Lars Alfredsson, Sofia Ernestam, Johan Askling, Saedis Saevarsdottir, Christina H. Opava, Xia Jiang, and Louise Hedenstierna

Subjects
Gerontology, Adult, Male, Immunology, MEDLINE, Arthritis, Rheumatoid, 03 medical and health sciences, Social support, 0302 clinical medicine, Rheumatology, Risk Factors, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Prospective Studies, Workplace, Aged, 030203 arthritis & rheumatology, Social stress, Sweden, business.industry, Incidence, Social Support, General Medicine, Middle Aged, medicine.disease, Decision latitude, Rheumatoid arthritis, Case-Control Studies, Female, business, Stress, Psychological
Abstract

Objectives: To investigate whether low social support or low decision latitude at work correlate with risk of rheumatoid arthritis (RA), and whether and how those factors are associated with known ...

Published
2021

38. Combined lifestyle factors and the risk of LADA and type 2 diabetes - Results from a Swedish population-based case-control study

Author

Katharina Herzog, Tiinamaija Tuomi, Rebecka Hjort, Josefin E. Löfvenborg, Lars Alfredsson, Emma Ahlqvist, Leif Groop, Sofia Carlsson, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Tiinamaija Tuomi Research Group, University Management, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, Department of Medicine, University of Helsinki, and Endokrinologian yksikkö

Subjects
Male, medicine.medical_specialty, ALCOHOL-CONSUMPTION, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Type 2 diabetes, LADA, 03 medical and health sciences, Autoimmune diabetes, 0302 clinical medicine, Endocrinology, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Family history, VALIDITY, education, Exercise, Latent Autoimmune Diabetes in Adults, Life Style, Sweden, education.field_of_study, business.industry, Case-control study, General Medicine, Odds ratio, ADULTS, ASSOCIATION, Middle Aged, medicine.disease, Lifestyle, Confidence interval, 3. Good health, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, GENE VARIANTS, Female, SMOKING, business
Abstract

Aims: We investigated the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes in relation to a healthy lifestyle, the proportion of patients attributable to an unhealthy lifestyle, and the influence of family history of diabetes (FHD) and genetic susceptibility. Methods: The population-based study included incident LADA (n = 571), type 2 diabetes (n = 1962), and matched controls (n = 2217). A healthy lifestyle was defined by BMI < 25 kg/m2, moderate-to-high physical activity, a healthy diet, no smoking, and moderate alcohol consumption. We estimated odds ratios (OR) with 95% confidence intervals (CIs) adjusted for age, sex, education, and FHD. Results: Compared to a poor/moderate lifestyle, a healthy lifestyle was associated with a reduced risk of LADA (OR 0.51, CI 0.34-0.77) and type 2 diabetes (OR 0.09, CI 0.05-0.15). A healthy lifestyle conferred a reduced risk irrespective of FHD and high-risk HLA genotypes. Having a BMI < 25 kg/m2 conferred the largest risk reduction for both LADA (OR 0.54, CI 0.43-0.66) and type 2 diabetes (OR 0.12, CI 0.10-0.15) out of the individual items. Conclusion: People with a healthy lifestyle, especially a healthy body weight, have a reduced risk of LADA including those with genetic susceptibility to diabetes. (C) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Published
2021

39. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno

Subjects
Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

40. Cognitive stimulation in the workplace, plasma proteins, and risk of dementia : three analyses of population cohort studies

Author

Jaana Pentti, Archana Singh-Manoux, Peter Westerholm, Marcel Goldberg, Adam G. Tabak, Tuula Oksanen, Jenni Ervasti, Ossi Rahkonen, Jane E. Ferrie, Pyry N Sipilä, Nina Mars, Rebecca F. Gottesman, Henrik Zetterberg, Gill Livingston, Anders Knutsson, Lars Alfredsson, Tea Lallukka, Joni V Lindbohm, Keenan A. Walker, Aki Koskinen, Ari Väänänen, Töres Theorell, Marie Zins, Jussi Vahtera, Jatinderpal Kalsi, Solja T. Nyberg, Stephen A. Williams, Mika Kivimäki, Olli Pietiläinen, Sakari Suominen, Clinicum, Department of Public Health, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, HUS Head and Neck Center, Helsinki Inequality Initiative (INEQ), Faculty Common Matters (Faculty of Social Sciences), Center for Population, Health and Society, and Staff Services

Subjects
Male, Neuropsychological Tests, Axonogenesis, 0302 clinical medicine, Risk Factors, Prospective Studies, Prospective cohort study, Workplace, Aged, 80 and over, 0303 health sciences, Incidence, Hazard ratio, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Blood Proteins, 3142 Public health care science, environmental and occupational health, ALZHEIMERS-DISEASE, Europe, Occupational Diseases, Cohort, alzheimer's disease, Female, Cohort study, medicine.medical_specialty, STRAIN, 03 medical and health sciences, strain, Internal medicine, medicine, Dementia, Humans, Occupations, 030304 developmental biology, Aged, Proportional Hazards Models, model, COMPLEXITY, Job strain, business.industry, Klinisk medicin, medicine.disease, Confidence interval, United Kingdom, United States, MODEL, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Clinical Medicine, Sedentary Behavior, business, complexity, 030217 neurology & neurosurgery
Abstract

Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. Design Multicohort study with three sets of analyses. Setting United Kingdom, Europe, and the United States. Participants Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. Main outcome measures Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. Results During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I 2 =0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β −0.34, P Conclusions The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Published
2021

41. The genetic structure of Norway

Author

Eivind Hovig, S. Sunna Ebenesersdóttir, Agnar Helgason, Tomas Olsson, Kristjan H. S. Moore, Ingrid Kockum, Kari Stefansson, Morten Mattingsdal, Thomas Hansen, Thomas Werge, Lars Alfredsson, and Ole A. Andreassen

Subjects
Population, Context (language use), Norwegian, Article, Gene flow, Danish, 03 medical and health sciences, Effective population size, Genetic variation, Genetics, Humans, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Polymorphism, Genetic, Norway, Ecology, 030305 genetics & heredity, language.human_language, Pedigree, Fixation (population genetics), Geography, Haplotypes, Genetic structure, language, Genetic markers, VDP::Samfunnsvitenskap: 200
Abstract

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity, and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway’s long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been an isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.

Published
2021

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

Author

Samuel Kuperman, Leila Karhunen, Geòrgia Escaramís, Sébastien Guillaume, Kelly L. Klump, David C. Whiteman, Colin A. Hodgkinson, Stephanie H. Witt, Artemis Tsitsika, Hana Papezova, Renato Polimanti, P. Eline Slagboom, Peter Zill, Jakob Grove, Toni-Kim Clarke, Michael Soyka, Jennifer Jordan, Steven Gallinger, Philip Gorwood, Preben Bo Mortensen, Yuri Milaneschi, Ingrid Meulenbelt, Jen Chyong Wang, Markus M. Nöthen, Katrin Männik, Henry R. Kranzler, Michael M. Vanyukov, Anna Keski-Rahkonen, William G. Iacono, Raymond K. Walters, Stephanie Le Hellard, Bochao Danae Lin, Vesna Boraska Perica, Marion Roberts, Patrick F. Sullivan, Steven Crawford, Mark A. Frye, Melissa A. Munn-Chernoff, Hakon Hakonarson, Andreas Birgegård, Robert Culverhouse, Alexis C. Edwards, Jerome C. Foo, Alessandro Rotondo, Brenda W.J.H. Penninx, Laura M. Hack, Michael T. Lynskey, Mario Maj, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Julie K. O'Toole, Marta Tyszkiewicz-Nwafor, Matt McGue, Julien Bryois, Martina de Zwaan, Norbert Dahmen, Stefanie Heilmann-Heimbach, Deborah Kaminská, Benedetta Nacmias, Nicholas G. Martin, Anna R. Docherty, Christopher Hübel, Nancy L. Pedersen, Janet Treasure, William E. Copeland, Roger A.H. Adan, Jaakko Kaprio, Aarno Palotie, L. John Horwood, Maria La Via, Philippe Courtet, Virpi M. Leppä, Judy L. Silberg, Jason D. Boardman, Fazil Aliev, Wade H. Berrettini, Doo Sup Choi, Youl-Ri Kim, Konstantinos Hatzikotoulas, Harriet de Wit, Sandra A. Brown, Elisabeth Widen, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Ralph E. Tarter, Jana Strohmaier, Allan S. Kaplan, Richard A. Grucza, Bradley T. Webb, Angela Favaro, Dalila Pinto, Helena Gaspar, Andrew W. Bergen, Beate Herpertz-Dahlmann, Robert Levitan, Wolfgang Gäbel, Xavier Estivill, Emma C. Johnson, Konstantinos Tziouvas, Lindsay A. Farrer, Lenka Foretova, Marc A. Schuckit, Joanna M. Biernacka, André Scherag, Robbee Wedow, Abraham A. Palmer, Amy E. Adkins, Franziska Degenhardt, Louisa Degenhardt, Jurjen J. Luykx, Marius Lahti-Pulkkinen, Brien P. Riley, Monika Ridinger, Matteo Cassina, Harry Brandt, Yiran Guo, Stephan Ripke, Palmiero Monteleone, Katri Räikkönen, Jonathan R. I. Coleman, Martin A. Kennedy, Stephen W. Scherer, Ioanna Tachmazidou, Catherine M. Olsen, Bernice Porjesz, Esther Walton, Yi-Ling Chou, Nicolas Ramoz, Tetsuya Ando, Andres Metspalu, Bertram Müller-Myhsok, Brion S. Maher, Sarah Bertelsen, Melanie L. Schwandt, Janiece E. DeSocio, Margaret Keyes, John F. Pearson, Dongbing Lai, Paul Lichtenstein, James MacKillop, George Dedoussis, Jari Lahti, Ulrike Schmidt, Stefan Ehrlich, Amanda G. Wills, Teemu Palviainen, David Goldman, Elena Tenconi, Dimitris Dikeos, Scott I. Vrieze, Sietske G. Helder, Katharina Buehren, Hongyu Zhao, Sara McDevitt, Jolanta Lissowska, Joseph M. Boden, Li-Shiun Chen, Susanne Lucae, Sara Marsal, Dan Rujescu, Claes Norring, Howard J. Edenberg, Victor M. Karpyak, Fragiskos Gonidakis, Per Hoffmann, Christopher S. Franklin, Karin Egberts, Johanna Giuranna, Stefan Herms, Leah Wetherill, Stephanie Zerwas, Anthony Batzler, Elliot C. Nelson, Jouke-Jan Hottenga, Marcella Rietschel, Ioanna Ntalla, Victor Hesselbrock, Sarah M. Hartz, Marie Navratilova, Falk Kiefer, Martien J H Kas, Richard J. Rose, Andrew C. Heath, Jin P. Szatkiewicz, Lenka Slachtova, Lisa Lilenfeld, Katherine A. Halmi, John P. Rice, Anjali K. Henders, Christian Dina, Norbert Wodarz, Satu Männistö, Hamdi Mbarek, Shuyang Yao, Vladimir Janout, Alison Goate, Bettina Konte, Alexandra Schosser, Danfeng Chen, Kirsty Kiezebrink, Euijung Ryu, Dana B. Hancock, James Mitchell, Sarah E. Medland, Ina Giegling, Valdo Ricca, Scott D. Gordon, Gabrielle Koller, Samuli Ripatti, Laura M. Thornton, Alison D. Murray, Morten Mattingsdal, Zeynep Yilmaz, Jens Treutlein, Kathleen K. Bucholz, Tim B. Bigdeli, Eric F. van Furth, Hermine H. Maes, Ken B. Hanscombe, Sandra Sanchez-Roige, Daniela Degortes, Monica Forzan, Manuel Mattheisen, Richard Sherva, Scott J. Crow, Mikael Landén, Wolfgang Herzog, Jeanette N. McClintick, Tõnu Esko, Louis Fox, Wolfgang Maier, Liselotte Petersen, Laura J. Bierut, Roseann E. Peterson, Gursharan Kalsi, Kathleen Mullan Harris, Margarita C T Slof-Op 't Landt, Tamara L. Wall, Patrik K. E. Magnusson, Unna N. Danner, Stephan Zipfel, Ulrich W. Preuss, Elisa Docampo, D. Blake Woodside, Alfonso Tortorella, Benjamin W. Domingue, Franziska Ritschel, Johan G. Eriksson, Anu Raevuori, Benjamin M. Neale, Marcus Ising, Annemarie A. van Elburg, Filip Rybakowski, Maureen Reynolds, Tracey D. Wade, Manfred M. Fichter, Monica Gratacos Mayora, Claudette Boni, Andreas J. Forstner, John Whitfield, Silviu Alin Bacanu, Matthew B. McQueen, Andrew M. McIntosh, Norbert Scherbaum, Tatiana Foroud, Gun Peggy Knudsen, Sven Cichon, Christian J. Hopfer, Josef Frank, Eleftheria Zeggini, Federica Tozzi, Nadia Micali, Danielle M. Dick, Pamela A. F. Madden, Christian R. Marshall, Johannes Hebebrand, Fernando Fernández-Aranda, Roel A. Ophoff, Roland Burghardt, Nathaniel Thomas, Leonid Padyukov, Nancy L. Saccone, Anu Loukola, Fabian Streit, James L. Kennedy, Jessica H. Baker, Peter McGuffin, Walter H. Kaye, Pei Hong Shen, Anne Farmer, Roger D. Cone, Ilka Boehm, Jacquelyn L. Meyers, Paolo Santonastaso, Maurizio Clementi, Susana Jiménez-Murcia, Gudrun Wagner, Anke Hinney, Richard Parker, James I. Hudson, Nathan A. Gillespie, Michael Strober, John I. Nurnberger, Sandro Sorbi, Dorret I. Boomsma, Beata Świątkowska, Janne Tidselbak Larsen, Kenneth S. Kendler, Hidetoshi Inoko, Jessica E. Salvatore, Hunna J. Watson, Jochen Seitz, Jacques Pantel, Karl Mann, Hang Zhou, Antonio Julià, Oliver S. P. Davis, Nancy Diazgranados, Krista Fischer, John K. Hewitt, Karen S. Mitchell, Joanna Hauser, Eric O. Johnson, Craig Johnson, E. Jane Costello, Agnieszka Słopień, Dong Li, Laramie E. Duncan, Arpana Agrawal, Grant W. Montgomery, Manuel Föcker, Thomas Werge, Lannie Ligthart, Andreas Karwautz, Raquel Rabionet, Kenneth Krauter, Joel Gelernter, James J. Crowley, Cynthia M. Bulik, Paola Giusti-Rodríguez, Laura M. Huckins, Gerome Breen, Michael C. Stallings, Daniel E. Adkins, Pierre J. Magistretti, John Kramer, Lars Alfredsson, Hartmut Imgart, Annette M. Hartmann, Ole A. Andreassen, Monika Dmitrzak-Weglarz, Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], QIMR Berghofer Medical Research Institute, Karolinska Institutet [Stockholm], University Children's Hospital of Essen [Essen, Germany], University of Duisburg-Essen, Aarhus University [Aarhus], Stockholm County Council, University of Würzburg, Guy's Hospital [London], University Medical Center [Utrecht], University of Gothenburg (GU), Altrecht Center for Eating Disorders Rintveld [Zeist, The Netherlands] (Mental Health Institute), National Institute of Mental Health [Tokyo, Japan] (NIMH), National Center of Neurology and Psychiatry [Tokyo, Japan], University of Oslo (UiO), Norwegian Centre for Mental Disorders Research [Oslo] (NORMENT), University of Oslo (UiO)-Haukeland University Hospital, University of Bergen (UiB)-University of Bergen (UiB)-Oslo University Hospital [Oslo], Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Perelman School of Medicine, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Split, The Wellcome Trust Sanger Institute [Cambridge], RWTH Aachen University, Universitätsklinikum Frankfurt, Universita degli Studi di Padova, University Hospital Basel [Basel], Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota System, University of Bristol [Bristol], Hannover Medical School [Hannover] (MHH), Harokopio University of Athens, Seattle University [Seattle], Virginia Commonwealth University (VCU), University of Athens Medical School [Athens], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Poznan University of Medical Sciences [Poland] (PUMS), Institute of Environmental Science and Technology [Barcelona] (ICTA), Universitat Autònoma de Barcelona (UAB), Massachusetts General Hospital [Boston], Stanford University, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Estonian Genome and Medicine, University of Tartu, Universitat Pompeu Fabra [Barcelona] (UPF), MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Ludwig-Maximilians-Universität München (LMU), Infectious diseases division, Department of internal medicine, University of Münster, Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Universitätsklinikum Bonn (UKB), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Medstar Research Institute, Universität Duisburg-Essen [Essen], National and Kapodistrian University of Athens (NKUA), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Psychiatric Genetic Unit, Poznan University of Medical Sciences, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Heidelberg University Hospital [Heidelberg], Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Parkland-Klinik [Bad Wildungen-Reinhardshausen, Germany], Tokai University, Department of Epidemiology and Public Health [university of Ostrava], Lékařská fakulta / Faculty of Medicine [University of Ostrava], Ostravská univerzita / University of Ostrava-Ostravská univerzita / University of Ostrava, Vall d'Hebron University Hospital [Barcelona], Charles University [Prague] (CU), University of Eastern Finland, Medizinische Universität Wien = Medical University of Vienna, Centre de toxicomanie et de santé mentale [Toronto, ON, Canada], University of Helsinki, University of Aberdeen, Faculty of Science, J.E. Purkinje University, J. E. Purkinje University, Michigan State University System, Norwegian Institute of Public Health [Oslo] (NIPH), Haukeland University Hospital, University of Bergen (UiB), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), The Chicago School of Professional Psychology [Washington, District of Columbia, USA] (Washington DC Campus), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Department of Psychiatry, University of Napoli, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], University College Cork (UCC), Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, VA Boston Healthcare System, Università degli studi della Campania 'Luigi Vanvitelli', Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Kartini Clinic [Portland, Oregon, USA], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Vanderbilt University School of Medicine [Nashville], The Hospital for sick children [Toronto] (SickKids), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Medical Epidemiology and Biostatistics (MEB), University of Pisa - Università di Pisa, Division of Psychiatric Genomics, Institute of Medical Informatics, Biometry and Epidemiology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Leiden University Medical Center (LUMC), Center for Eating Disorders Ursula [Leiden, The Netherlands] (Rivierduinen), Medical University of Łódź (MUL), The Jackson Laboratory [Bar Harbor] (JAX), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Human Genetics, Internal Medicine [Tuebingen, Germany], Tuebingen University [Germany], Oregon Research Institute (ORI), University of Otago [Dunedin, Nouvelle-Zélande], The Center for Eating Disorders at Sheppard Pratt [Baltimore, MD, USA], Weill Medical College of Cornell University [New York], Eating Recovery Center [Denver, CO, USA], Centre for Addiction and Mental Health [Toronto, ON, Canada], University of California [San Diego] (UC San Diego), University of California, Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Institute of Medical Science [Toronto], University of Toronto, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Genomics, Yale University School of Medicine, Indiana University School of Medicine, Indiana University System, Mayo Clinic [Rochester], Mayo Clinic, SUNY Downstate Medical Center, State University of New York (SUNY), University of Edinburgh, Department of Genomics, Life and Brain Center, University of Bonn, University of Utah School of Medicine [Salt Lake City], University of Heidelberg, Medical Faculty, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], National Institutes of Health [Bethesda] (NIH), National Institute on Alcohol Abuse and Alcoholism [Bethesda, MD, USA] (NIAAA), Martin-Luther-University Halle-Wittenberg, Helsinki Institute of Life Science (HiLIFE), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Vrije Universiteit Amsterdam [Amsterdam] (VU), Mathematical Sciences Institute (MSI), Australian National University (ANU), University of Colorado [Boulder], VU University Medical Center [Amsterdam], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Universität Heidelberg [Heidelberg], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Harvard University [Cambridge], University of Colorado Anschutz [Aurora], University of Vermont [Burlington], University of New South Wales [Sydney] (UNSW), University of Dusseldorf, Genetics and Pathology, Center for Human Genetic Research, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Heidelberg University, University of Iowa [Iowa City], Vienna University of Technology (TU Wien), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Indiana University System-Indiana University System, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Regensburg, Rush University Medical Center [Chicago], University of Utah, Duke University Medical Center, University of Illinois [Chicago] (UIC), University of Illinois System, Department of Medical and Molecular Genetics, Dpt of Neuroscience [New York], Laboratory of Neurogenetics, National Institutes of Health [Bethesda] (NIH)-National Institute on Alcohol Abuse and Alcoholism, Department of Health and Human Services, University of Connecticut (UCONN), University of Colorado [Denver], Research Triangle Institute International (RTI International), McMaster University [Hamilton, Ontario], CLinical Psychology, Department of Electrical and Computer Engineering [Montréal], McGill University = Université McGill [Montréal, Canada], Yale School of Public Health (YSPH), Analytic and Translational Genetics Unit, Flinders University [Adelaide, Australia], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Department of Public Health, Indiana University - Purdue University Indianapolis (IUPUI), National Institute of Mental Health (NIMH), University of Pennsylvania, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Università degli Studi di Padova = University of Padua (Unipd), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), King‘s College London-The Institute of Psychiatry, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Masaryk Memorial Cancer Institute (MMCI), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Università degli Studi di Firenze = University of Florence (UniFI), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Medical Research Council-Cardiff University, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Martinez Rico, Clara, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Kas lab, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Munn-Chernoff, M. A., Johnson, E. C., Chou, Y. -L., Coleman, J. R. I., Thornton, L. M., Walters, R. K., Yilmaz, Z., Baker, J. H., Hubel, C., Gordon, S., Medland, S. E., Watson, H. J., Gaspar, H. A., Bryois, J., Hinney, A., Leppa, V. M., Mattheisen, M., Ripke, S., Yao, S., Giusti-Rodriguez, P., Hanscombe, K. B., Adan, R. A. H., Alfredsson, L., Ando, T., Andreassen, O. A., Berrettini, W. H., Boehm, I., Boni, C., Boraska Perica, V., Buehren, K., Burghardt, R., Cassina, M., Cichon, S., Clementi, M., Cone, R. D., Courtet, P., Crow, S., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J. E., Dick, D. M., Dikeos, D., Dina, C., Dmitrzak-Weglarz, M., Docampo, E., Duncan, L. E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Farmer, A., Favaro, A., Fernandez-Aranda, F., Fichter, M. M., Fischer, K., Focker, M., Foretova, L., Forstner, A. J., Forzan, M., Franklin, C. S., Gallinger, S., Giegling, I., Giuranna, J., Gonidakis, F., Gorwood, P., Gratacos Mayora, M., Guillaume, S., Guo, Y., Hakonarson, H., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S. G., Herms, S., Herpertz-Dahlmann, B., Herzog, W., Huckins, L. M., Hudson, J. I., Imgart, H., Inoko, H., Janout, V., Jimenez-Murcia, S., Julia, A., Kalsi, G., Kaminska, D., Karhunen, L., Karwautz, A., Kas, M. J. H., Kennedy, J. L., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K. L., Knudsen, G. P. S., La Via, M. C., Le Hellard, S., Levitan, R. D., Li, D., Lilenfeld, L., Lin, B. D., Lissowska, J., Luykx, J., Magistretti, P. J., Maj, M., Mannik, K., Marsal, S., Marshall, C. R., Mattingsdal, M., Mcdevitt, S., Mcguffin, P., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, K., Monteleone, A. M., Monteleone, P., Nacmias, B., Navratilova, M., Ntalla, I., O'Toole, J. K., Ophoff, R. A., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Pinto, D., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Ripatti, S., Ritschel, F., Roberts, M., Rotondo, A., Rujescu, D., Rybakowski, F., Santonastaso, P., Scherag, A., Scherer, S. W., Schmidt, U., Schork, N. J., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M. C. T., Slopien, A., Sorbi, S., Swiatkowska, B., Szatkiewicz, J. P., Tachmazidou, I., Tenconi, E., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tyszkiewicz-Nwafor, M., Tziouvas, K., van Elburg, A. A., van Furth, E. F., Wagner, G., Walton, E., Widen, E., Zeggini, E., Zerwas, S., Zipfel, S., Bergen, A. W., Boden, J. M., Brandt, H., Crawford, S., Halmi, K. A., Horwood, L. J., Johnson, C., Kaplan, A. S., Kaye, W. H., Mitchell, J., Olsen, C. M., Pearson, J. F., Pedersen, N. L., Strober, M., Werge, T., Whiteman, D. C., Woodside, D. B., Grove, J., Henders, A. K., Larsen, J. T., Parker, R., Petersen, L. V., Jordan, J., Kennedy, M. A., Birgegard, A., Lichtenstein, P., Norring, C., Landen, M., Mortensen, P. B., Polimanti, R., Mcclintick, J. N., Adkins, A. E., Aliev, F., Bacanu, S. -A., Batzler, A., Bertelsen, S., Biernacka, J. M., Bigdeli, T. B., Chen, L. -S., Clarke, T. -K., Degenhardt, F., Docherty, A. R., Edwards, A. C., Foo, J. C., Fox, L., Frank, J., Hack, L. M., Hartmann, A. M., Hartz, S. M., Heilmann-Heimbach, S., Hodgkinson, C., Hoffmann, P., Hottenga, J. -J., Konte, B., Lahti, J., Lahti-Pulkkinen, M., Lai, D., Ligthart, L., Loukola, A., Maher, B. S., Mbarek, H., Mcintosh, A. M., Mcqueen, M. B., Meyers, J. L., Milaneschi, Y., Palviainen, T., Peterson, R. E., Ryu, E., Saccone, N. L., Salvatore, J. E., Sanchez-Roige, S., Schwandt, M., Sherva, R., Streit, F., Strohmaier, J., Thomas, N., Wang, J. -C., Webb, B. T., Wedow, R., Wetherill, L., Wills, A. G., Zhou, H., Boardman, J. D., Chen, D., Choi, D. -S., Copeland, W. E., Culverhouse, R. C., Dahmen, N., Degenhardt, L., Domingue, B. W., Frye, M. A., Gaebel, W., Hayward, C., Ising, M., Keyes, M., Kiefer, F., Koller, G., Kramer, J., Kuperman, S., Lucae, S., Lynskey, M. T., Maier, W., Mann, K., Mannisto, S., Muller-Myhsok, B., Murray, A. D., Nurnberger, J. I., Preuss, U., Raikkonen, K., Reynolds, M. D., Ridinger, M., Scherbaum, N., Schuckit, M. A., Soyka, M., Treutlein, J., Witt, S. H., Wodarz, N., Zill, P., Adkins, D. E., Boomsma, D. I., Bierut, L. J., Brown, S. A., Bucholz, K. K., Costello, E. J., de Wit, H., Diazgranados, N., Eriksson, J. G., Farrer, L. A., Foroud, T. M., Gillespie, N. A., Goate, A. M., Goldman, D., Grucza, R. A., Hancock, D. B., Harris, K. M., Hesselbrock, V., Hewitt, J. K., Hopfer, C. J., Iacono, W. G., Johnson, E. O., Karpyak, V. M., Kendler, K. S., Kranzler, H. R., Krauter, K., Lind, P. A., Mcgue, M., Mackillop, J., Madden, P. A. F., Maes, H. H., Magnusson, P. K. E., Nelson, E. C., Nothen, M. M., Palmer, A. A., Penninx, B. W. J. H., Porjesz, B., Rice, J. P., Rietschel, M., Riley, B. P., Rose, R. J., Shen, P. -H., Silberg, J., Stallings, M. C., Tarter, R. E., Vanyukov, M. M., Vrieze, S., Wall, T. L., Whitfield, J. B., Zhao, H., Neale, B. M., Wade, T. D., Heath, A. C., Montgomery, G. W., Martin, N. G., Sullivan, P. F., Kaprio, J., Breen, G., Gelernter, J., Edenberg, H. J., Bulik, C. M., and Agrawal, A.

Subjects
Netherlands Twin Register (NTR), Alcoholism/genetics, Schizophrenia/genetics, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Medicine (miscellaneous), Genome-wide association study, Alcohol use disorder, Anorexia nervosa, Linkage Disequilibrium, ddc:616.89, [SCCO]Cognitive science, 0302 clinical medicine, Risk Factors, Tobacco Use Disorder/genetics, Substance-Related Disorders/genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Factors de risc en les malalties, Bulimia nervosa, Feeding and Eating Disorders/genetics, eating disorders, genetic correlation, substance use, Tobacco Use Disorder, 3. Good health, Fenotip, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Alcoholism, Eating disorders, Phenotype, Schizophrenia, Drinking of alcoholic beverages, eating disorder, Consum d'alcohol, Major depressive disorder, medicine.symptom, Depressive Disorder, Major/genetics, eating disorders, genetic correlation, substance use, Clinical psychology, Substance abuse, Risk factors in diseases, Substance-Related Disorders, Polymorphism, Single Nucleotide, Article, Feeding and Eating Disorders, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Genetics, medicine, Humans, Trastorns de la conducta alimentària, 030304 developmental biology, Genetic association, Pharmacology, Depressive Disorder, Major, Binge eating, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, [SCCO] Cognitive science, medicine.disease, Comorbidity, Twin study, 030227 psychiatry, Abús de substàncies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, business, Genètica, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

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 (BN) and problem alcohol use (genetic correlation [rg], 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 BN 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 (MDD). Total sample sizes per phenotype ranged from ~2,400 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 (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; qwith binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to −0.23; qs

Published
2021

43. Sleep problems in rheumatoid arthritis over 12 years from diagnosis: results from the Swedish EIRA study

Author

Lauren Lyne, Torbjörn Åkerstedt, Lars Alfredsson, Tiina Lehtonen, Saedis Saevarsdottir, Lars Klareskog, and Helga Westerlind

Subjects
Sleep Wake Disorders, Sweden, Immunology, Rheumatoid Arthritis, Arthritis, Rheumatoid, Rheumatology, patient reported outcome measures, Humans, Medicine, Immunology and Allergy, epidemiology, Sleep, Pain Measurement
Abstract

ObjectiveMost studies of rheumatoid arthritis (RA) and sleep have focused on established RA. We here investigate sleep quality and sleep duration in patients with newly diagnosed RA and during 1–12 years after diagnosis.MethodsData were collected on sleep 1–12 years after diagnosis from patients diagnosed 1998–2018 in the Swedish study Epidemiological Investigation of RA. Six sleep domains (sleep problems, non-restorative sleep, insomnia, insufficient sleep, sleep quality perceived as poor and sleep considered a health problem); a global sleep score and time spent in bed were estimated. Using logistic regression, ORs were calculated for each sleep outcome by disease duration. We explored whether pain (low (Visual Analogue Scale=0–20 mm, reference), intermediate=21–70, high=71–100) or functional impairment (Health Assessment Questionnaire>1.0) was associated with problems.ResultsWe had sleep data on 4131 observations (n=3265 individuals). Problems with ≥1 sleep domain (global sleep score) was reported in 1578 observations (38%) and increased with disease duration (OR 1.04, 95% CI 1.02 to 1.07). Median time in bed was 8 hours (Q1-Q3: 7.5–9.0). High-grade pain increased the likelihood of sleep problems ~3–9 fold, and increased functional impairment ~4–8 fold.ConclusionIn this cohort of newly diagnosed patients with RA with access to the current treatment from diagnosis, we did not find any major problems with sleep, and existing sleep problems related mainly to pain and reduced function. Treatment of sleep problems in RA should be guided towards treating the underlying problem causing the sleep disturbance.

Published
2022

44. Anti–Citrullinated Protein Antibody Specificities, Rheumatoid Factor Isotypes, and Incident Cardiovascular Events in Patients With Rheumatoid Arthritis

Author

Guy Serre, Lars Alfredsson, Linda Mathsson-Alm, Johan Rönnelid, Karl Skriner, Monika Hansson, Martin Cornillet, Per-Johan Jakobsson, Helga Westerlind, Johan Askling, Rikard Holmdahl, Saedis Saevarsdottir, Lars Klareskog, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Karolinska Institutet [Stockholm], Uppsala University, Karolinska University Hospital [Stockholm], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Immunology, Genetics and Pathology [Uppsala, Sueden] (IGP), Rheumatology Unit, and Medical Inflammation Research

Subjects
0301 basic medicine, Male, Anti-Citrullinated Protein Antibodies, Arthritis, Rheumatoid, 0302 clinical medicine, Antibody Specificity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, skin and connective tissue diseases, Stroke, ComputingMilieux_MISCELLANEOUS, biology, Kransæðasjúkdómar, Incidence, Hazard ratio, Anti–citrullinated protein antibody, Middle Aged, Cardiovascular disease, 3. Good health, Immunoglobulin Isotypes, Cardiovascular Diseases, Rheumatoid arthritis, Female, Adult, musculoskeletal diseases, medicine.medical_specialty, Acute coronary syndrome, Immunology, 03 medical and health sciences, Rheumatology, Rheumatoid Factor, Internal medicine, Rheumatoid factor, Humans, Aged, Rheumatology and Autoimmunity, 030203 arthritis & rheumatology, Sweden, Reumatologi och inflammation, business.industry, Proportional hazards model, medicine.disease, 030104 developmental biology, Case-Control Studies, biology.protein, Iktsýki, business, Mace
Abstract

Publisher's version (útgefin grein), Objective: To investigate the relationship between anti–citrullinated protein antibodies (ACPAs), specific ACPA subspecificities, rheumatoid factor (RF) isotypes, and incident cardiovascular (CV) events in patients with rheumatoid arthritis (RA). Methods: Serum samples from Swedish patients with new-onset RA (diagnosed within 1 year of symptom onset between 1996 and 2009) were centrally typed for anti–cyclic citrullinated peptide 2 (anti-CCP2) antibodies, 20 ACPA subspecificities, and RF isotypes. Patients were followed up longitudinally in nationwide registers to monitor the occurrence of acute coronary syndrome (ACS), stroke, CV-related death, and major adverse CV events (MACE). The association between each serologic marker and CV outcome, and the impact of adjustment for the Disease Activity Score in 28 joints (DAS28), smoking status, and income at baseline, were assessed using Cox proportional hazards models. In addition, associations of serologic markers with all-cause mortality were explored. Results: In total, 2,814 patients with RA were included in the study. The median follow-up was 13 years, during which the CV end points of ACS, stroke, or CV-related death were reported to occur in 375 patients. Occurrence and/or levels of anti-CCP2 were associated with risk of incident ACS (hazard ratio [HR] 1.46, 95% confidence interval [95% CI] 1.03–2.06), stroke (HR 1.47, 95% CI 1.03–2.10), CV-related death (P = 0.024 for association with anti-CCP2 levels), and MACE (HR 1.34, 95% CI 1.06–1.70). Similarly, an association with the number of ACPA subspecificities was observed; however, this could not be attributed to any individual or group of ACPA subspecificities. Presence of IgM-RF was associated with all CV end points except ACS, and IgA-RF was exclusively associated with CV-related death. Adjustment for smoking status, income, and DAS28 scores decreased most of the HRs, whereas IgA-RF remained associated with CV-related death (HR 1.61, 95% CI 1.05–2.48). All of the assessed serologic makers were associated with all-cause mortality. Conclusion: RF isotypes and ACPAs are associated with future CV events in patients with RA. ACPA levels and number of subspecificities seem more important than the occurrence of particular subspecificities, and these associations were not explained by a history of ever smoking., Karolinska institutet (strategic research area epidemiology), The nordic research council (nordforsk), The rheumatology research foundation (foreum), Stiftelsen för Strategisk Forskning, Vetenskapsrådet, Stockholms Läns Landsting, The swedish heart lung foundation

Published
2020

45. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen

Subjects
Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2020

46. Insufficient Sun Exposure Has Become a Real Public Health Problem

Author

Richard Weller, Pelle G. Lindqvist, Frank R. de Gruijl, Cedric F. Garland, Ramune Jacobsen, David G. Hoel, Prue H. Hart, David J. Llewellyn, Rajiv Chowdhury, Martin Feelisch, Henning Tiemeier, Lars Alfredsson, Antony R. Young, D. Allan Butterfield, Bruce K. Armstrong, Butterfield, D Allan [0000-0003-3254-5286], Hart, Prue H [0000-0001-7207-6467], Hoel, David G [0000-0002-1178-1610], Jacobsen, Ramune [0000-0002-8142-9807], Lindqvist, Pelle G [0000-0002-1652-8235], Weller, Richard B [0000-0003-2550-9586], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, Ultraviolet Rays, Health, Toxicology and Mutagenesis, lcsh:Medicine, Sunburn, vitamin D, Disease, Review, UV radiation, 030207 dermatology & venereal diseases, 03 medical and health sciences, sun exposure, 0302 clinical medicine, Breast cancer, nitric oxide, Environmental health, medicine, Vitamin D and neurology, Humans, Asthma, Type 1 diabetes, integumentary system, business.industry, Public health, lcsh:R, disease prevention, Public Health, Environmental and Occupational Health, medicine.disease, Vitamin D Deficiency, Europe, Sunlight, Public Health, Metabolic syndrome, business, 030217 neurology & neurosurgery
Abstract

This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer’s disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5–30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR.

Published
2020
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47. No association between moist oral snuff (snus) use and oral cancer: pooled analysis of nine prospective observational studies

Author

Cecilia Magnusson, Lars Alfredsson, Patrik Wennberg, Anders Knutsson, Ylva Trolle Lagerros, Rino Bellocco, Margareta Norberg, Maria Rosaria Galanti, Gunnar Engström, Anton Lager, Nancy L. Pedersen, Marzieh Araghi, Per-Olof Östergren, Michael Lundberg, Weimin Ye, Zhiwei Liu, Araghi, M, Galanti, M, Lundberg, M, Liu, Z, Ye, W, Lager, A, Engstrom, G, Alfredsson, L, Knutsson, A, Norberg, M, Wennberg, P, Lagerros, Y, Bellocco, R, Pedersen, N, Ostergren, P, and Magnusson, C

Subjects
Male, medicine.medical_specialty, Tobacco, Smokeless, 03 medical and health sciences, Tobacco Use, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Snuff, Prospective Studies, Risk factor, Proportional Hazards Models, Sweden, business.industry, Oral cancer, Incidence (epidemiology), Confounding, Hazard ratio, Public Health, Environmental and Occupational Health, Cancer, smokeless tobacco, General Medicine, medicine.disease, snu, 030220 oncology & carcinogenesis, Snus, incidence, Mouth Neoplasms, business, Cohort study
Abstract

Aims: Worldwide, smokeless-tobacco use is a major risk factor for oral cancer. Evidence regarding the particular association between Swedish snus use and oral cancer is, however, less clear. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between snus use and oral cancer. Methods: A total of 418,369 male participants from nine cohort studies were followed up for oral cancer incidence through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. Results: During 9,201,647 person-years of observation, 628 men developed oral cancer. Compared to never-snus use, ever-snus use was not associated with oral cancer (adjusted HR 0.90, 95% CI: 0.74, 1.09). There were no clear trends in risk with duration or intensity of snus use, although lower intensity use (⩽ 4 cans/week) was associated with a reduced risk (HR 0.65, 95% CI: 0.45, 0.94). Snus use was not associated with oral cancer among never smokers (HR 0.87, 95% CI: 0.57, 1.32). Conclusions: Swedish snus use does not appear to be implicated in the development of oral cancer in men.

Published
2020

48. Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking

Author

Johan Askling, Lars Klareskog, Helga Westerlind, Marie Holmqvist, Vanessa L. Kronzer, Fredrik Nyberg, Göran Tornling, Cynthia S. Crowson, and Lars Alfredsson

Subjects
Adult, Male, medicine.medical_specialty, Immunology, Respiratory Tract Diseases, Arthritis, Disease, Anti-Citrullinated Protein Antibodies, Arthritis, Rheumatoid, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Rheumatology, Rheumatoid Factor, Risk Factors, Internal medicine, Epidemiology, medicine, Odds Ratio, Immunology and Allergy, Rheumatoid factor, Humans, 030212 general & internal medicine, Respiratory Tract Infections, Aged, 030203 arthritis & rheumatology, Sweden, business.industry, Respiratory disease, Smoking, Odds ratio, Middle Aged, medicine.disease, Asthma, Logistic Models, Rheumatoid arthritis, Acute Disease, Chronic Disease, Female, business, Lung Diseases, Interstitial, Body mass index
Abstract

Objective The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Methods Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Results Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Conclusion Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.

Published
2020

49. Obesity-Related Traits and the Development of Rheumatoid Arthritis: Evidence From Genetic Data

Author

Lars Klareskog, Lars Alfredsson, Bowen Tang, Huwenbo Shi, Xia Jiang, and Leonid Padyukov

Subjects
0301 basic medicine, Male, Linkage disequilibrium, Immunology, Population, Full Length, Rheumatoid Arthritis, Genetic correlation, Polymorphism, Single Nucleotide, White People, Body Mass Index, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Mendelian randomization, Odds Ratio, Immunology and Allergy, Medicine, Body Size, Humans, Obesity, education, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Waist-Hip Ratio, Mendelian Randomization Analysis, Odds ratio, Confidence interval, Causality, 030104 developmental biology, Female, business, Body mass index, Demography
Abstract

OBJECTIVE To investigate the association between obesity-related traits and risk of rheumatoid arthritis (RA). METHODS We conducted genetic correlation analysis and a 2-sample Mendelian randomization (MR) study, using genome-wide genetic data based on >850,000 individuals of European ancestry. Summary statistics were collected from the largest genome-wide association study conducted to date for body mass index (BMI; n = 806,810), waist-to-hip ratio (WHR; n = 697,734), WHR adjusted for BMI (WHRadjBMI; n = 694,649), and RA (ncase = 14,361, ncontrol = 43,923). We conducted cross-trait linkage disequilibrium score regression and ρ-HESS analyses to quantify genetic correlation between pairs of traits (causal overlap). For each obesity-related exposure, we utilized independent, genome-wide significant single-nucleotide polymorphisms (P < 5 × 10-9 ) as instruments to perform MR analysis (causal relationship). We interrogated the causal relationship both in the general population and in a sex-specific manner and calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Sensitivity analyses were performed to validate MR model assumptions. RESULTS Despite a negligible overall genetic correlation between the 3 obesity-related traits and RA, we found significant local genetic correlations at several regions on chromosome 6 (positions 28-29M, 30-35M, and 50-52M), highlighting a shared genetic basis. We further observed an increased risk of RA per SD increment (4.8 kg/m2 ) in genetically predicted BMI (OR 1.22 [95% CI 1.09-1.37]). The effect was consistent across sensitivity analyses and comparable between sexes (OR 1.22 [95% CI 1.04-1.44] in male subjects and 1.19 [95% CI 1.04-1.36] in female subjects). However, we did not find evidence supporting a causal role of either WHR (OR 0.98 [95% CI 0.84-1.14]) or WHRadjBMI (OR 0.90 [95% CI 0.79-1.04]) in RA. CONCLUSION Genetically predicted BMI significantly increases RA risk. Future studies are needed to understand the biologic mechanisms underlying this link.

Published
2020

50. Pregnancy does not modify the risk of MS in genetically susceptible women

Author

Lars Alfredsson, Lisa F. Barcellos, Steffan D. Bos, Ingrid Kockum, Anny H. Xiang, Xiaorong Shao, Sean L. Wu, Edlin Gonzales, Kalliope H. Bellesis, Patrick T. Bradshaw, Catherine Schaefer, Tomas Olsson, Terrence Chinn, Jessica B. Smith, Cameron Adams, Annette Langer-Gould, and Marte Wendel-Haga

Subjects
Adult, Risk, Multiple Sclerosis, Physiology, Logistic regression, White People, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, Genetic Predisposition to Disease, Registries, Age of Onset, Allele, Reproductive History, 030304 developmental biology, Sweden, 0303 health sciences, Norway, business.industry, Middle Aged, Random effects model, medicine.disease, United States, Regression, Neurology, Cohort, Female, Gene-Environment Interaction, Neurology (clinical), Live birth, Parity (mathematics), business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo use the case-only gene-environment (G E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.MethodsWe studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.ResultsEvidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.ConclusionOur findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

Published
2020
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