Recent research has identified genes linked to educational attainment, but their effects on subsequent socioeconomic outcomes, particularly in egalitarian Nordic welfare states, remain largely unexplored. We analyze two genetically informed Finnish datasets, encompassing longitudinal register information on earnings, employment, unemployment, occupational status, and social assistance receipt (n = 31,622). We examine the role of a polygenic score for educational attainment (EA PGS), achieved level of education, and family socioeconomic background in predicting these outcomes in adulthood. We further study cohort differences around Finland's comprehensive school reform of the 1970s that aimed to promote equality of opportunity. Our results show that in the post-reform generation, EA PGS did not significantly predict adulthood outcomes after controlling for the achieved level of education. A notable exception was for occupational status. In contrast, in the pre-reform generation, EA PGS predicted later socioeconomic outcomes beyond education, indicating relationships not fully explained by schooling. Parental income did not moderate the effect of the EA PGS. Our findings shed additional light on the mechanisms connecting genetic factors and life chances, demonstrating that institutional setting and schooling can shape the influence of genetic endowment for high educational attainment in adult socioeconomic status.

BACKGROUND:Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis. METHODS:We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis. FINDINGS:Our analysis revealed four genome-wide significant (p < 5 × 10-8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant. INTERPRETATION:We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol. FUNDING:This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.

Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the systemic plasma lipidomic, proteomic and DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. Individuals with CeD on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with daily 100 mg ZED1227 drug (PGCd, n = 28) or placebo (PGCp, n = 19). Samples were collected at baseline (GFD) and post-gluten challenge (PGC). Mass spectrometry-based lipidomic and proteomics profiling were applied to plasma samples matched with duodenal histology. Whole blood samples (drug, n = 20; placebo, n = 16) were subjected to DNA methylation analysis. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin. Significantly different gluten-induced plasma lipidomic changes were detected between GFD vs. PGCp and between GFD vs. PGCd, with 46 lipids differentially expressed in the placebo group and 6 in the drug group suggesting that the ZED1227 normalized gluten-induced lipidomic changes in plasma. Changes in medium-chain fatty acylcarnitines (CARs), particularly CAR 10:1 and CAR 9:0, were correlated with transient, non–clinically significant changes in renal biomarkers, with kidney function remaining within the normal range in the PGCp group. Glomerular filtration rate and plasma creatinine were restored with ZED1227. Integrated multi-omics analysis revealed a coordinated immune–epigenetic–lipid module centered on Ficolin-2, PUFA-enriched triglycerides, and a tightly co-regulated CpG cluster in the PER3 circadian regulator gene, highlighting selective immunometabolic coupling independent of clinical stratification. Drug treatment revealed consistent patterns suggesting normalization of the proteome and DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge. These findings provide evidence that ZED1227 can significantly prevent the gluten-induced CeD-associated systemic changes in plasma/blood. EudraCT 2017-002241-30.

DNA methylation-based epigenetic clocks have been highlighted as promising biomarkers of ageing, and they have been shown to robustly predict morbidity and mortality. However, current literature is lacking a formal analysis of the increased prediction accuracy, or the added value, of the epigenetic clocks over traditional risk factors, such as body composition, smoking, or alcohol consumption, in predicting common chronic diseases. Here, we have compared the most commonly used epigenetic clocks and traditional risk factors as predictors of incidence of ageing-associated non-communicable chronic disease in a 7-to-9-year follow-up in a middle-aged population cohort (n = 1108, aged 34 to 49 years at baseline). In our cohort, a statistical model consisting of a combination of traditional risk factors (age, sex, smoking, alcohol consumption, WHR, BMI) outperforms any model including an epigenetic clock. The added value of epigenetic clock measurements over simple and affordable traditional risk factors should be clearly established if epigenetic clocks are to be used in clinical settings or as tools of personal health monitoring.

Socioeconomic disadvantage at individual level is associated with poor cognitive outcomes but the link of neighborhood disadvantage with cognitive function is unclear. We used data from Young Finns Study, a population-based cohort, to examine the associations of neighborhood and individual-level disadvantage in childhood (age 3-21 years) and adulthood (age 22 up to the time of cognitive assessment) with cognitive function in mid-adulthood (age 35-49 years). Neighborhood disadvantage was ascertained based on register data, including geo-coded address history. Compared to individuals who experienced neither individual-level nor neighborhood disadvantage in childhood, those who experienced both had, on average, 0.236 SDs lower overall cognitive function scores (95% CI: -0.355 to -0.116) and those who experienced individual-level but not neighborhood disadvantage had 0.196 SDs lower scores (95% CI, -0.323 to -0.070). The estimates were slightly larger for adult individual-level and neighborhood disadvantage. The findings were similar across the cognitive domains and robust to adjustment for a polygenic risk score for cognitive ability. We found no clear evidence of sleep difficulties, depressive symptoms or cardiovascular health mediating the associations. Our findings suggest that socioeconomic disadvantage at individual-level but not neighborhood-level, from childhood to adulthood, may impact on cognitive function in mid-adulthood.

Background and aims: Direct evidence to connect early life metabolism with cardiometabolic diseases in old age is limited due to the rarity of multi-decadal biochemical follow-up studies. To gain deeper insight into metabolic ageing, we conducted a longitudinal study that integrates serial data on clinical biomarkers, metabolomics and clinical events across the human life course. Methods: Children born in 1962-1992 were included from four European cohorts. Time-series of clinical biomarkers and metabolomics data were available for 8,653 participants (ages 0-49 years, 142 molecular and four physiological variables). Comparable data for 13,795 UK Biobank participants at two visits (ages 40-79 years) were linked with retrospective and prospective records of diabetes and cardiovascular disease. Lifetime metabolic trajectories were reconstructed by unsupervised machine learning and local polynomial regression. Results: A stable stratification in metabolic health emerged in children between ages 3 and 12 years and persisted to old age. We summarized this population pattern by assigning each participant into one of seven metabolic subgroups with characteristic biomarker trajectories. Two subgroups (MetDys TG+ and MetDys TG-) featured increased waist-height ratio from childhood, persistently higher C-reactive protein throughout life and rapidly increasing fasting insulin between 30 and 49 years of age. Both subgroups exhibited high risk for diabetes (HR > 13) and ischemic heart disease (HR > 2.5) when compared against the lowest risk subgroup (High HDL ApoB-). Conclusions: This life-course analysis shows that metabolic dysfunction associated with excess weight gain begins in early childhood and is associated with cardiometabolic morbidity in later life. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement V-PM was supported by the University of Oulu Profi8 Health Dimensions programme and Research Council of Finland Decision 365202. This study was also supported by a research grant from the Sigrid Juselius Foundation, the Finnish Foundation for Cardiovascular Research, and the Research Council of Finland (grant #357183 and Profi8 #365202). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (URL: http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Specific grants that apply here include 076467/Z/05/Z, CS/15/6/31468, 086676/Z/08/Z, 076467/Z/05/Z, 076467/Z/05/Z, PG106/145 and R01 DK077659. This publication is the work of the authors and V-P Makinen will serve as the guarantor for the contents of this paper. The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study did not involve recruitment of study subjects or new biomedical experiments. Ethical approval for ALSPAC was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. The STRIP was approved by the joint Committee of Ethics of the University of Turku and the University Central Hospital of Turku on Nov 8th 1989. The YFS was approved by the ethical committees for five Finnish universities with medical schools (Regional Committee on Medical Research Ethics of the HUS Joint Authority for Helsinki, Regional Medical Research Ethics Committee of Eastern Finland for Kuopio, Northern Ostrobothnia Hospital District Ethical Committee for Oulu, the Ethics Committee of the Wellbeing Services County of Pirkanmaa for Tampere and the Ethics Committee of the Wellbeing Services County of Southwest Finland for Turku). The NFBC1966 study was approved by the Northern Ostrobothnia Hospital District Ethical Committee, Finland (94/2011, Dec 12th 2011). The UK Biobank was approved by the North West Multi-centre Research Ethics Committee (21/NW/0157, Jun 29th 2021) with details available online [https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics]. For ALSPAC, consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of all data collected was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Participants can contact the study team at any time to retrospectively withdraw consent for their data to be used. Study participation is voluntary and during all data collection sweeps, information was provided on the intended use of data. Specific Research Ethics Committee approval is sought for the consenting process at each collection sweep. Written consent, including permission for future use, is obtained from adult participants or from the parents of children as appropriate. Ethical approval for future use is covered by ALSPAC's Research Tissue Bank approval. All historical consents to hold biological samples have been reviewed as part of the Tissue Bank approval process. Participants can contact the study team at any time to retrospectively withdraw consent for use of their samples. For STRIP, written informed consent was obtained from parents at study entry, and from the participants at ages 15, 18, and 26 years. For YFS, NFBC1966 and UK Biobank, written informed consent was also obtained. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in the manuscript are available either as biobank resources or by material transfer request from the cohort curators.

Both short and long sleep duration have been associated with poor glycemic control and an increased risk of developing type 2 diabetes mellitus. Although sleep duration may differentially modify the effects of genetic risk factors for type 2 diabetes, this has not been systematically investigated. In the present study, we conducted genome-wide gene by sleep duration meta-analyses, separately assessing interactions of short and long sleep, for fasting glucose, fasting insulin, and hemoglobin A1c in up to 489,309 individuals without diabetes from seven different population groups. In total, 16 loci were identified to interact with sleep duration - six with short sleep and ten with long sleep. Of these, four loci were identified through cross-population meta-analysis. Mapped genes exhibit pathway connections to pericyte apoptosis, NMDA receptor activity, the GLUT1 receptor, neurological health, and sleep architecture. Eleven loci (VRK2, PCDH7, TFAP2A, CAP2, PAPPA, ZCCHC2, MYH9, SGIP1, JAKMIP3, RRAS2, MAPT) have not been reported in previous glycemic trait genome-wide association studies. Interaction loci identify divergent biological mechanisms for short and long sleep duration influencing glycemic control, suggesting specific pathways of intervention for precision medicine approaches to diabetes prevention and management.

We investigate whether childhood adiposity affects adulthood earnings via education, using Finnish genotyped data and a causal mediation design. A one unit increase in childhood BMI, which corresponds to transitioning from normal weight to overweight, or from overweight to obesity, reduces adult earnings by approximately 23% through lower educational attainment. Our results further suggest that early-life adiposity has long-term economic consequences that are independent of adult weight.

Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5×10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5×10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol's influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

Prospective studies have demonstrated an inverse association between lipoprotein(a) [Lp(a)] levels and the risk for type 2 diabetes, although the mechanisms underlying this relationship remain unclear. We examined the associations of Lp(a) with incident type 2 diabetes, fasting serum insulin, and fasting plasma glucose, in the prospective Young Finns Study cohort. Lp(a) measurements were first available in Young Finns Study participants in 1986 (N = 2 464). For type 2 diabetes analyses, the baseline was defined as the 2001 follow-up study (participants aged 24–39 years) when data on both Lp(a) and diabetes status were available (N = 2 263). The association between Lp(a) levels and incident type 2 diabetes was examined using the Fine-Gray model. Associations with fasting insulin and glucose were analyzed using repeated-measures linear regression, utilizing data from 1986, 2001, 2007, 2011, and 2018. During the mean follow-up period of 16.6 years from 2001, 144 participants (6.4

Aim: Tobacco smoking induces persistent DNA methylation (DNAm) changes in blood that can serve as long-term biomarkers for smoking exposure. We aimed to develop and validate a DNAm classifier of smoking status using Illumina EPIC array data. Methods: We built Epigenetic Smoking status Estimator2 (EpiSmokEr2), a Least Absolute Shrinkage and Selection Operator (LASSO) regression-based DNAm classifier using 511 CpGs from Illumina Infinium MethylationEPIC array (EPIC) data. The model was trained on 1343 samples from the Young Finns Study cohort and validated across six independent datasets from four cohorts and two array platforms (EPIC and EPICv2). Results: EpiSmokEr2 achieved an average sensitivity of 0.87 and specificity of 0.86 in distinguishing current from never smokers. Predicted smoking status correlated strongly with established DNAm smoking scores and GrimAge, indicating its ability to capture biologically relevant smoking effects. Simulation analysis showed EpiSmokEr2 was robust for up to 10% missing CpGs. Conclusion: EpiSmokEr2 provides a reliable DNAm-based estimator of smoking status. It is available as an open-source R package on GitHub, facilitating broad use in epidemiological and clinical research.

We examined whether the accumulation of psychosocial risk factors (socioeconomic risks, health behavioural risks, stressful life-events and psycho-emotional risks) in childhood and adolescence contributes to insufficient social relations (loneliness, frequency and heterogeneity of social contacts and social support) in adulthood participants from the longitudinal Young Finns Study with a 38-year follow-up (N = 1787, 56% female). Results from regression models indicated that a higher cumulative number of risks in childhood and adolescence was associated (1-SD increase) with higher loneliness (B = 0.32, 95% CI 0.19 ; 0.45), lower perceived social support (B=-0.32, 95% CI -0.45 ; -0.19), lower frequency of social contacts (B = 0.19, 0.06 ; 0.32), and lower heterogeneity in social contacts (B=-0.33, -0.47 ; -0.20) in midlife. Causal mediation analysis suggested that depressive symptoms partially mediate the relationship between cumulative childhood and adolescent psychosocial risks and adult social relations (mediation proportion range between 7% and 18%). Educational attainment mediated the relationship between cumulative psychosocial risk and social relations heterogeneity by 8%, while income mediated the association with loneliness, social support and social relations heterogeneity by 9% to 11%. In conclusion, this study underscores the potentially profound and lasting impact of psychosocial risks encountered during childhood and adolescence on social relations in adulthood.

DNA methylation-based epigenetic clocks are reliable measures of biological age and aging rate. Chronic inflammation may contribute to aging and various diseases, but population-based studies on specific inflammatory biomarkers’ impact on epigenetic clocks are limited. The aim of this study was to investigate the associations between 38 circulating inflammatory biomarkers, as well as a combined systemic inflammation variable, and epigenetic clocks in a middle-aged population. The cohort included 1,327 Finnish participants (aged 30–45 years, 50–55% female) from the Young Finns Study. Biomarkers were measured in 2007, and epigenetic clocks were assessed in 2011 and 2018. DunedinPACE and PCGrimAgeDev clocks were calculated using blood methylation data. Multiple linear regression models adjusted for age, sex, BMI, smoking, socioeconomic status, alcohol consumption, and physical activity were used. Results showed 11 biomarkers positively associated with DunedinPACE across both follow-ups. Seven biomarkers were positively associated with PCGrimAgeDev in the 4-year follow-up, but not in the 11-year follow-up. The combined systemic inflammation marker was positively associated with both clocks in both follow-ups. Although previous cross-sectional studies have reported associations between pro-inflammatory cytokines and epigenetic ageing, longitudinal findings remain sparse. Our results extend this literature by showing that several cytokines predict accelerated epigenetic ageing across an 11-year follow-up.

AIMS:P-wave prolongation and left atrial (LA) enlargement are markers of atrial cardiomyopathy and increase the risk for atrial fibrillation, stroke, and mortality. We investigated whether the cumulative burden of cardiovascular risk factors in early life is associated with P-wave duration and LA size in middle age. METHODS AND RESULTS:The Cardiovascular Risk in Young Finns Study is a prospective, ongoing, multicentre cohort initiated in 1980. Traditional cardiovascular risk factors were assessed repeatedly between 1980 and 2001 (ages 6-24 years), and transthoracic echocardiography and electrocardiography were performed in 2011. Associations between cumulative early life risk factors and P-wave duration, LA diameter, and LA volume were analysed using logistic regression. Body mass index (BMI) was the main modifiable determinant of P-wave prolongation and LA enlargement. Each standard deviation (SD) increase in early life BMI burden was associated with longer P-wave duration (0.120 SD; 1.85 ms), larger LA diameter (0.264 SD; 0.11 cm), and greater LA volume (0.235 SD; 3.31 mL). Male sex associated with all studied P-wave and LA parameters and older age associated with larger LA diameter. Higher physical activity in middle age was associated with 0.116 SD increased LA volume (1.64 mL). Participants with persistent or adult-onset high BMI were more likely to have larger LA. CONCLUSION:Excess BMI from childhood through adulthood is a key determinant of atrial remodelling in middle age. These findings highlight the long-term impact of early life adiposity and underscore the importance of lifelong weight management in preventing atrial cardiomyopathy and its clinical sequelae.

Abstract Background Previous trauma research includes many limitations, such as the scarcity of pretraumatic health measurements and assessment of traumatic experiences with a broad scope across the lifespan. To respond to these gaps, we aimed to develop a new, prospective, population-based trauma dataset from childhood to middle age. Methods We used the Young Finns Study that is a population-based, multi-generational, prospective study (n = 3596 for the main generation). It has started in 1980 (baseline assessment) and includes follow-ups in 1983, 1986, 1989, 1992, 1997, 2001, 2007, 2011/2012, and 2018–2020. From the 38-year follow-up and ten measurement points of the YFS, we collected all relevant trauma variables, including both free-format and structured questions that both the participants and their parents responded to. By a data-driven case-to-case analysis, we developed a scale to numerically capture variation in the quality of the experiences. Results Our final dataset captured a total of 7769 traumatic experiences. We also developed the Traumatic Experience Severity Scale (TESS), including six subscales such as shamefulness, rarity, danger to life or health, effects on everyday life, human-made physical threat, and whether the target person was within or outside one’s household. We also preprocessed the dataset to be later easily interleaved with other psychological, cardiovascular, and epigenetic variables of the YFS. Conclusions We believe this new trauma dataset with thousands of experiences across the lifespan provides new opportunities to multidisciplinary, lifelong trauma research.

Apolipoprotein A-IV (apoA-IV) plays key roles in lipid metabolism, reverse cholesterol transport, and kidney function, yet its genetic determinants remain poorly defined. We conduct a genome-wide association study (GWAS) meta-analysis of apoA-IV concentrations measured by ELISA in 25,181 individuals and combine these with proteomic data from 33,995 UK Biobank participants (Olink platform), yielding a total sample of 59,176. We perform genetic correlations and colocalization analyses to explore links with lipid, renal, and other complex traits. The GWAS identifies several novel loci to be associated with apoA-IV concentrations (TDRD5, DPP4, MYL3, MORC1, MCUB, GATA4, ZPR1, UMOD, GLP2R, SLC38A10 and APOE) besides two previously identified loci (APOA5-A4-C3-A1 cluster and KLKB1). Cross-platform comparison shows strong concordance of effect directions and magnitudes, underscoring the robustness of findings across measurement techniques. Global genetic correlation reveals significant shared genetic architecture between apoA-IV, kidney function and HDL-cholesterol, while colocalization supports shared causal variants with lipid, renal, and hematological phenotypes, suggesting biologically relevant pathways. These results provide a comprehensive overview of the genetic architecture of apoA-IV and suggest mechanistic links to lipid metabolism, kidney function and blood-related traits. Our findings refine the role of apoA-IV as a potential biomarker and inform future epidemiological research.

BACKGROUND:Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. OBJECTIVE:We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. METHODS:Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. RESULTS:Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10-6), with two reaching genome-wide significance: rs116936231 (FGL1) in adult doctor-diagnosed FA plus food-specific sensitization phenotype (stable after additional hay fever adjustment) and rs8022829 (AKAP6-NPAS3), which was significant only in the hay fever-adjusted model in adults. However, neither variant was validated. Further, we identified 3 single nucleotide polymorphisms previously reported for FA and atopic disease. CONCLUSION:This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies.

Schizophrenia is characterized by weaker test-measured cognitive performance, which is partially explained by disease-related secondary factors (after the onset of the disorder) such as side effects of antipsychotics, stigma, or sedentary behavior. We examined whether polygenic risk for schizophrenia (PRSSCZ) is associated with (a) test-measured or (b) self-reported cognitive performance in individuals who have not converted into non-affective psychosis during follow-up to extending to middle age. The participants came from the population-based Young Finns Study, born between 1962 and 1977 (n = 2217). Participants with diagnosed non-affective psychoses were excluded from the sample. Diagnoses collected from the Care Register for Health Care. PRSSCZ was calculated on the basis of the most recent genome-wide association study on schizophrenia. Cognitive performance was measured with (1) subtests of the Cambridge Neuropsychological Test Automated Battery, measuring visuospatial learning, reaction time, sustained attention, and executive function and (2) self-reported executive functions including distractibility, task orientation, and rigidity. In individuals who have not developed non-affective psychoses during follow-up to middle age, high PRSSCZ was associated with lower scores in all test-measured cognitive domains. These associations sustained after controlling for health behaviors and socioeconomic factors. PRSSCZ was not associated with self-reported distractibility or task orientation but was related to an increasing trajectory of rigidity when approaching middle age. We observed lower cognitive functioning in domains similar to those reported in studies of patients with schizophrenia. Thus, some difficulties in cognitive performance may not be fully attributable to the disorder itself but may partly reflect normative developmental trajectories in individuals with high polygenic liabilities. Not applicable.

Adolescent healthy behaviours may improve cardiometabolic health in adulthood differently across socioeconomic groups. We aimed to quantify the effects of adolescent healthy behaviours on multiple biomarkers of adult cardiometabolic health by socioeconomic backgrounds. We used a population-based cohort of Finnish adolescents from the Young Finns Study (1980–89, n = 2984) followed into adulthood (2001–11). Healthy behaviours (no smoking, no alcohol consumption, sufficient physical activity, daily fruit and vegetable consumption) and socioeconomic backgrounds (parental- and neighbourhood-related) were measured in adolescence (12–18 years). Biomarkers of adiposity [waist circumference, body mass index (BMI)], cardiovascular [blood pressure (BP), cholesterol, apolipoprotein B], and metabolic [plasma glucose, insulin resistance] outcomes were measured in adulthood (33–40 years). We estimated conditional average effects of healthy behaviours via inverse-probability-weighted marginal structural models. Sufficient physical activity lowered adiposity biomarkers to a greater extent among adolescents from disadvantaged neighbourhood, with additional decreases of 2.2 cm [95% confidence interval (CI): −0.1 to 4.7] in waist circumference and 1 kg/m2 (95% CI: 0.2 to 1.9) in BMI. In contrast, daily fruit and vegetable consumption lowered BP with additional 2.0–3.6 mmHg (95% CI: 0.3 to 6.1) among adolescents with advantaged either parental or neighbourhood socioeconomic backgrounds. There was little evidence for differential effects on other outcomes and for no smoking and alcohol. Socioeconomic backgrounds modified the effects of adolescent physical activity and fruit and vegetable consumption on adult cardiometabolic health. These findings indicate that population-wide interventions promoting healthy behaviours during adolescence have the potential to either mitigate or exacerbate long-term socioeconomic inequalities in cardiometabolic health.

Blastocyst culture is an essential part of IVF/ICSI treatments, however, it has been shown to increase the risk of preterm deliveries as well as large for gestational age infants. The effect of the extended culture on offspring phenotype is thought to be mediated by epigenetic mechanisms, since this developmental period coincides with extensive epigenetic remodelling. Here, we compare genome-wide DNA methylation of cord blood and umbilical cord artery samples collected from newborns resulting from cleavage-stage transfer (n = 25), blastocyst-stage transfer (n = 25), and spontaneous conception (n = 30). Epigenome-wide association studies, global methylation analyses, and epigenetic age comparison did not reveal statistically significant differences between the cleavage-stage and blastocyst-stage groups. However, we identified some loci with a >10% difference in median methylation level between the groups, which should be studied further with a larger sample size. The genome-wide DNA methylation of spontaneously conceived and cleavage-stage newborns were comparable while in the spontaneous to blastocyst-stage comparison, cg25263722 was differentially methylated (P = 5 × 10-8) in umbilical cord artery. Our study did not identify major effects of extended culture on DNA methylation, which is reassuring with respect to the future health of newborns conceived via assisted reproductive technologies.