Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Large registry-based analysis of genetic predisposition to tuberculosis identifies genetic risk factors at HLA.

Tuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1895 individuals in the FinnGen study had International Classification of Diseases-based tuberculosis diagnosis. Genome-wide association study analysis identified genetic variants with statistically significant association with tuberculosis at the human leukocyte antigen (HLA) region (P < 5e-8). Fine mapping of the HLA association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (P = 1.82E-06, OR = 0.81 [CI 95% 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (P = 0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (P < 0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted P < 0.05, OR = 1.83 [CI 95% 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.

The impact of Mendelian sleep and circadian genetic variants in a population setting.

Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.

Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects.

BACKGROUND: Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database. RESULTS: We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327. CONCLUSIONS: Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Tobacco endgame goals and measures in Europe: current status and future directions.

The European Union (EU) aims for a tobacco use prevalence of less than 5% by 2040 with its Tobacco-Free Generation goal, aligning with the tobacco endgame approach. In the Joint Action on Tobacco Control 2 (JATC-2) -project, we examined adopted and planned endgame goals and measures as well as preparedness to counter tobacco industry interference in the process. We surveyed key informants in 24 out of 50 countries in the WHO European Region (19 of the 27 EU Member States, MS). Altogether, eight countries (7 EU MS) had official governmental endgame goals, and an additional six EU MS had similar proposals from government, civil society or research entities. Movement towards tobacco endgame was most evident in retail-oriented and consumer-oriented policies. These include restricting the sales of tobacco and related products and raising the age limit above 18 years. Product standards were used especially to regulate flavours but no measures to substantially reduce addictiveness were reported. Market-oriented measures that tap into industry profits were predominantly missing, and countries often lacked concrete tools to prevent industry interference. Respondents' concerns around tobacco endgame were related to high smoking prevalence in some population groups, non-combustible and new nicotine products, cross-border marketing, political will, challenges with the existing regulations and industry interference. Results indicate both momentum and challenges in adopting and disseminating measures that facilitate achieving tobacco endgame goals. The EU goal can be used to advocate for national endgame goals and measures, and for the strengthened implementation of the WHO Framework Convention on Tobacco Control.

Cross-sectional study of the associations between the implementation of the WHO FCTC tobacco advertising, promotion and sponsorship bans and current e-cigarette use among youth from countries with different income levels.

BACKGROUND: The WHO Framework Convention on Tobacco Control (WHO FCTC) Article 13 requires countries to ban tobacco advertising, promotion and sponsorship (TAPS), and bans are recommended to cover electronic cigarettes (e-cigarettes). We examined youth e-cigarette prevalence by TAPS regulations in countries with different income levels. METHODS: We analysed data on 165 299 respondents from 48 countries with 2016/2018 WHO FCTC implementation reports and 2016-2019 Global Youth Tobacco Survey. We used multilevel logistic regressions to examine associations between TAPS regulations and current e-cigarette use, stratified by country income. RESULTS: About 1 in 10 respondents was currently using e-cigarettes. Respondents in countries with TAPS bans on the internet were less likely to use e-cigarettes (adjOR=0.58; 95% CI 0.39 to 0.86) than youth in countries without such bans. In lower middle-income and low-income countries, bans on displaying tobacco products at the point of sale (adjOR=0.55; 95% CI 0.34 to 0.90), bans on product placement (adjOR=0.44; 95% CI 0.28 to 0.69) and strength of additional TAPS measures were associated with lower prevalence of e-cigarette use among students. Being taught about the dangers of the use of tobacco in school was associated with lower odds of e-cigarette use. No differences in the use of e-cigarettes were observed by types of TAPS among respondents in high-income countries. CONCLUSIONS: Strengthening implementation of TAPS policies and assuring they cover new and emerging products, online channels and points of sales are essential, especially in lower income countries. Maintaining tobacco health education is also important to protect youth from e-cigarette use.

Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Evaluation of C4 Gene Copy Number in Pediatric Acute Neuropsychiatric Syndrome.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.

Exclusive and dual use of electronic cigarettes among European youth in 32 countries with different regulatory landscapes.

BACKGROUND: The Tobacco Products Directive (2014/40/EU) partially harmonised the regulation of electronic cigarettes (e-cigarettes) in Europe, but individual countries maintain jurisdiction over bans on use in public places, domestic advertising, taxation and flavour regulations. Their association with youth e-cigarette use has not been examined. METHODS: We used the cross-sectional 2019 European School Survey Project on Alcohol and Other Drugs data from 32 countries with 98 758 students aged 15-16 years and the 2020 WHO's assessment of the e-cigarette regulations. Multilevel logistic regression models on ever (vs never) and current (vs non-current) exclusive e-cigarette use, exclusive cigarette use and dual use by e-cigarette regulations' composite score were adjusted for age, gender, parental education, perceived family's financial well-being, perceived difficulty of obtaining cigarettes, country income level and general progress in tobacco control. RESULTS: Of the respondents, 13.3% had ever used cigarettes, 10.6% e-cigarettes and 27.3% both; 13.0% currently used cigarettes, 6.0% e-cigarettes and 6.4% both. Higher composite country score in the e-cigarette regulations was associated with lower current exclusive e-cigarette use (OR=0.78; 95% CI 0.65 to 0.94) and current dual use (OR=0.80; 95% CI 0.67 to 0.95). Youth perceiving more difficulties in obtaining cigarettes were less likely to use cigarettes, e-cigarettes and both ever and currently (OR from 0.80 (95% CI 0.76 to 0.85) to 0.94 (95% CI 0.92 to 0.96)). CONCLUSIONS: More comprehensive e-cigarette regulations and enforcement of age-of-sale laws may be protective of e-cigarette and dual use among adolescents.

Area-level sociodemographic differences in tobacco availability examined with nationwide tobacco product retail licence data in Finland.

BACKGROUND: Differences in tobacco retailer density between areas by sociodemographic composition have been observed. However, little research comes from European jurisdictions and from countries with a tobacco retail licensing system. In Finland, the system consists of criteria for retailers and supervision fees. METHODS: The tobacco product retail licence data and sociodemographic data were retrieved from corresponding Finnish authorities. Area-level tobacco availability was measured as the presence of a retailer and as the number of retailers per 1000 inhabitants by postcode area. Sociodemographic indicators included median income, percentage of inhabitants in the lowest income tertile, percentage of adults with higher education and unemployment rate. Analyses were based on logistic regression and Ordinary Least Squares regression with log-transformed density. RESULTS: Lower area-level sociodemographic composition was mainly associated with higher tobacco availability. Income was the strongest correlate of the tobacco retailer availability: areas with higher median income had lower odds of having a tobacco retailer (OR 0.54, 95% CI 0.48 to 0.61 per €1000) and lower retailer density (-4.4% per €1000, Cohen's f=0.51). Areas with a greater proportion of people in the lowest income category had higher densities of tobacco retailers (+2.8% per percentage point, Cohen's f=0.07). Other sociodemographic indicators showed inconsistent associations with retailer presence and density. CONCLUSION: Tobacco availability can be higher in areas with lower sociodemographic composition also in a country with a comprehensive tobacco retail licensing system and small income inequalities. Retailing policies should be further developed to reduce tobacco availability and narrow inequalities in tobacco use.

Towards Tobacco-Free Generation: implementation of preventive tobacco policies in the Nordic countries.

AIMS: Europe's Beating Cancer Plan set a goal of creating a Tobacco-Free Generation in Europe by 2040. Prevention is important for achieving this goal. We compare the Nordic countries' preventive tobacco policies, discuss the possible determinants for similarities and differences in policy implementation, and provide strategies for strengthening tobacco prevention. METHODS: We used the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) to identify the key policies for this narrative review. We focused on Articles 6, 8, 9, 11, 13 and 16 of the WHO FCTC, and assessed the status of the required (core) and recommended (advanced) policies and their application to novel tobacco and nicotine products. Information on the implementation of strategies, acts and regulations were searched from global and national tobacco control databases, websites and scientific articles via PubMed and MEDLINE. RESULTS: The WHO FCTC and European regulations have ensured that the core policies are mostly in place, but also contributed to the shared deficiencies that are seen especially in the regulations on smokeless tobacco and novel products. Strong national tobacco control actors have facilitated countries to implement some advanced policies - even as the first countries in the world: point-of-sale display bans (Iceland), outdoor smoking bans (Sweden), flavour bans on electronic cigarettes (Finland), plain packaging (Norway), and plain packaging on electronic cigarettes (Denmark). CONCLUSIONS: Collaboration and participation in reinforcing the European regulations, resources for national networking between tobacco control actors, and national regulations to provide protection from the tobacco industry's interference are needed to strengthen comprehensive implementation of tobacco policies in the Nordic countries.

Changes in smoking due to COVID-19 pandemic among persons of migrant origin compared with the general population: a population-based study.

AIMS: Prior studies have implied that smokers may have changed their smoking behaviour during the COVID-19 pandemic. However, little is known about changes in smoking behaviour and correlates of change due to the pandemic among persons of migrant origin compared with the general population. METHODS: Population-based cross-sectional studies with comparable study protocols and measures, one focusing on persons of migrant origin living in Finland (n = 3587, response rate 60%) and the other on the general Finnish population (n = 3444, response rate 56%), were utilised. The outcome measure was self-reported change in smoking behaviour due to COVID-19 among current smokers. Explanatory factors included sociodemographic-, health-, and COVID-19-related factors. Multinomial logistic regression was used in the analyses. RESULTS: Most of the current smokers reported no change in their smoking behaviour. In the adjusted model, younger age was positively associated with increased smoking, while region of origin (Russia, Africa, Asia, and Latin America) and worrying about getting infected with COVID-19 were associated with decreased smoking among persons of migrant origin. In the general population, younger age, female sex, being other than employed/student, increased loneliness, and decreased contact with close ones were associated with increased smoking, while reduced working capacity and worries that someone close to the respondent will be infected with COVID-19 were associated with decreased smoking. CONCLUSIONS: The findings of this study contribute to better identification of at-risk populations in future crises situations. This will allow for more efficient targeting and tailoring of health promotion services, including smoking cessation.

Changes in prevalence and sociodemographic correlates of tobacco and nicotine use in Finland during the COVID-19 pandemic.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on tobacco and nicotine use remains debated. We examined whether the prevalence of tobacco and nicotine use and nicotine-replacement therapy (NRT) changed during the COVID-19 pandemic and whether changes differed by sociodemographic groups. METHODS: Repeated cross-sectional study of three national surveys in Finland (2018, 2019 and 2020; n = 58 526 adults aged 20 and over). Outcomes were daily and occasional smoking, smokeless tobacco (snus) use, e-cigarettes use, total tobacco or nicotine use and NRT use. We examined changes for each outcome by sex, age, educational tertiles, marital status, mother tongue and social participation. RESULTS: Daily smoking decreased among males by 1.15 percentage points (pp) [95% confidence interval (CI) -2.10 to -0.20] between 2018 and 2020 and 0.86 pp among females (95% CI -1.58 to -0.15). Daily snus use remained stable in both sexes. Daily e-cigarette use was below 1% and remained stable. We found weak evidence of a reduction in total tobacco or nicotine use between 2018 and 2020 (males -1.18 pp, 95% CI -2.68 to 0.32 and females -0.8 pp, 95% CI -1.81 to 0.22). NRT use remained stable. Snus and NRT use decreased among 60- to 74-year-olds but remained stable in other age groups. We did not find evidence of interactions by subgroup for other outcomes. CONCLUSIONS: Daily smoking decreased in Finland between 2018 and 2020, but other forms of tobacco use did not experience a reduction. The COVID-19 pandemic does not seem to have altered the sustained reduction of smoking in Finland, although substantial sociodemographic differences persist.

Association of accelerometer-derived sleep measures with lifetime psychiatric diagnoses: A cross-sectional study of 89,205 participants from the UK Biobank.

BACKGROUND: Sleep problems are both symptoms of and modifiable risk factors for many psychiatric disorders. Wrist-worn accelerometers enable objective measurement of sleep at scale. Here, we aimed to examine the association of accelerometer-derived sleep measures with psychiatric diagnoses and polygenic risk scores in a large community-based cohort. METHODS AND FINDINGS: In this post hoc cross-sectional analysis of the UK Biobank cohort, 10 interpretable sleep measures-bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration-were derived from 7-day accelerometry recordings across 89,205 participants (aged 43 to 79, 56% female, 97% self-reported white) taken between 2013 and 2015. These measures were examined for association with lifetime inpatient diagnoses of major depressive disorder, anxiety disorders, bipolar disorder/mania, and schizophrenia spectrum disorders from any time before the date of accelerometry, as well as polygenic risk scores for major depression, bipolar disorder, and schizophrenia. Covariates consisted of age and season at the time of the accelerometry recording, sex, Townsend deprivation index (an indicator of socioeconomic status), and the top 10 genotype principal components. We found that sleep pattern differences were ubiquitous across diagnoses: each diagnosis was associated with a median of 8.5 of the 10 accelerometer-derived sleep measures, with measures of sleep quality (for instance, sleep efficiency) generally more affected than mere sleep duration. Effect sizes were generally small: for instance, the largest magnitude effect size across the 4 diagnoses was ß = -0.11 (95% confidence interval -0.13 to -0.10, p = 3 × 10-56, FDR = 6 × 10-55) for the association between lifetime inpatient major depressive disorder diagnosis and sleep efficiency. Associations largely replicated across ancestries and sexes, and accelerometry-derived measures were concordant with self-reported sleep properties. Limitations include the use of accelerometer-based sleep measurement and the time lag between psychiatric diagnoses and accelerometry. CONCLUSIONS: In this study, we observed that sleep pattern differences are a transdiagnostic feature of individuals with lifetime mental illness, suggesting that they should be considered regardless of diagnosis. Accelerometry provides a scalable way to objectively measure sleep properties in psychiatric clinical research and practice, even across tens of thousands of individuals.

Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn's disease via altered methylation and expression of EPHB4-a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10-4), Crohn's disease (rg = 0.097 ± 0.06, P = 3.27 × 10-3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10-3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10-3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10-3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10-3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health.

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p<5.0×10-8): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near FTO (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.

HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

BACKGROUND: The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated. METHODS: Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes. RESULTS: Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10- 11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10- 10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR = 1.14, p = 2.34 × 10- 9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR = 1.18, p = 5.86 × 10- 10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions. CONCLUSIONS: Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

Autoimmunity in narcolepsy.

PURPOSE OF REVIEW: Summarize the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development. RECENT FINDINGS: Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development. SUMMARY: Narcolepsy is a severe sleep disorder, in which neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy, and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.

Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.

Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9) beta -1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10) OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.