Background and Aims To elucidate the genetic architecture of blood pressure (BP) and heart rate (HR) during early life and assess their potential relevance to adult health outcomes.Methods The largest genome-wide association study (GWAS) meta-analyses to date of childhood systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (n = 28 425) and HR (n = 22 565) were conducted in children of European ancestry aged 4-17 years. Follow-up analyses included comparisons with adult GWAS results, polygenic risk score (PRS) analyses in independent cohorts of diverse ancestries, and a phenome-wide association study in the UK Biobank.Results Eight genome-wide significant loci were identified for childhood BP (KIAA2013, CACNB2, PLCE1, PAX2, COL4A2, RP11-236L14.1, CFDP1, TPX2) and three loci for childhood HR (CCDC141, ACHE, MYH6); all novel in children but previously reported in adults. Childhood PRSs explained up to 1.6% of BP variance and 5.2% of HR variance among children of European ancestry. Genetic correlations between childhood and adulthood BP traits were moderate (rg = 0.4-0.7), suggesting age-specific genetic effects on BP. In the UK Biobank, higher childhood BP PRS levels were significantly associated with a broad range of adult health outcomes, particularly cardiometabolic outcomes such as hypertension, angina, myocardial infarction, and cardiovascular disease-related mortality.Conclusions These findings advance the understanding of the genetic architecture of childhood BP and HR and provide compelling genetic evidence linking childhood BP to a broad spectrum of adult health outcomes-particularly cardiometabolic conditions-which may inform targeted prevention strategies from a young age.

Abstract Background 39M children worldwide are overweight or have obesity, accelerating risk for adult non-communicable diseases. Presently, interventions to prevent obesity have had limited success due to poor timing and lack of personalisation. Objective We aimed to identify early-life predictors of childhood obesity (ChOB) that could aid targeting specific population subsets for obesity prevention interventional studies. Methods: Data were from the Raine Study Gen2 participants (n=1494). Anthropometric and genetic predictors evaluated included birthweight (BW), early-life BMI (1-3 years), and three polygenic scores (PGS) [two BW-PGSs (BW-PGS 2016 and BW-PGS 2019 ) and a ChOB-PGS], developed from BW and ChOB genome-wide-association-studies, respectively. Multivariate analyses were performed to investigate associations between predictors and child-BMI (5-, 8- , 10-years). Results: BW-PGS 2019 associate with child-BMI at 5-years. BW-PGS 2016 was not associated with child-BMI. Remaining predictors positively associate with child-BMI at 5-, 8- and 10-years (p<0.001). Early-life BMI, ChOB-PGS and BW accounted for up to 38.7%, 5.8% and 3.4% of the variability in child-BMI, respectively. Conclusions Our data suggest early-life BMI is a better predictor of child-BMI than ChOB-PGS, and BW, accounting for up to ten-fold more variance in child-BMI. Future interventional studies to mitigate obesity could target early-life BMI as a marker to identify children at the highest risk. Practitioner Points (up to 3 key points) 1. Birthweight is associated with later-life obesity, but it is a variable predictive marker. Polygenic scores (PGS) provide additional insight into obesity and overweight risk in adulthood. Little is known about other predictors that could provide insight into the risk of later-life obesity. 2. Early-life BMI (before 3-years of age) predicts childhood obesity better than genetic and birthweight markers, accounting for more variance. Interventions to prevent obesity could now be more appropriately targeted. 3. Early-life BMI is a better predictor of child BMI than birthweight or childhood obesity PGS, which could aid obesity risk-stratification and ensure interventions to prevent obesity are targeted to children who will most benefit.

Problem Despite numerous public health initiatives, rates of exclusive breastfeeding in Australia do not meet recommendations. Background Currently 35% of maternity services provide some form of continuity of care, with superior results in key outcomes. Aim This pilot study was undertaken to determine feasibility of a lactation consultant led continuity of care model for breastfeeding support. Methods Randomisation occurred at 36-weeks gestation. Usual care followed NSW Health guidelines, the new model provided support by a board-certified lactation consultant, with up to 14 postnatal appointments available until six months postpartum. The primary outcome was study feasibility, measured by recruitment and retention, and protocol adherence. Secondary outcomes were breastfeeding rates at discharge, 4-months and 6-months postpartum. Findings Recruitment uptake was high, over 95% of women approached enrolled in the study, with 90.1% completing the study protocol. Attrition was < 10% and rates of monthly data collection completion varied between 45% and 88%. The intervention utilised 225 service hours. End point data at 6-months was available for 88.9% (intervention) and 84.8% (usual care) of participants. Discussion Despite higher rates of breastfeeding issues, women in the intervention group had similar rates of breastfeeding at 4- and 6-months and reduced hospital readmissions for breastfeeding related issues. Women indicated a preference for text and phone support once breastfeeding was established, however this preference may need to be balanced with more in-person support to ensure maximum benefits. Conclusion Outcomes indicate a larger RCT using this protocol would be feasible, with an economic evaluation recommended.

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.

BACKGROUND:The Barker hypothesis, that poor fetal growth can program adult cardiometabolic disease, has been contradicted by genetic investigations that demonstrate direct pleiotropic effects from birthweight genetics on cardiometabolic risk. We investigated if the cardiometabolic effects of birthweight genetics were dependent on the birthweight phenotype of the offspring. METHODS:Repeated measures of adult body mass index, insulin resistance, low-density lipoprotein cholesterol and systolic blood pressure were modeled in a cohort of 1167 offspring followed from mid-pregnancy through to age 27. In linear mixed-effects models, we tested the associations of birthweight polygenic scores in the presence of a high vs low birthweight phenotype. RESULTS:Here we show that a birthweight phenotype-genotype mismatch associates with central adiposity and insulin resistance in young adults. In fetuses that fail to reach their growth potential (i.e. low phenotypic birthweight with high birthweight polygenic score) we find increased central adiposity and insulin resistance. In those that exceed their growth potential (high phenotypic birthweight with low birthweight polygenic score), data suggests increased insulin resistance. We find no evidence of phenotype-genotype mismatch influence on low-density lipoprotein cholesterol and systolic blood pressure. CONCLUSION:These data support the Barker hypothesis, and we suggest it is the deviation from fetal growth potential rather than crude BW that underpins the relationship with adult disease risk. Identification of individuals with a birthweight phenotype-genotype mismatch could allow early identification of children at future risk.

The choroid is critical for maintaining vision and implicated in several ocular diseases, being the sole source of nutrients and waste removal for the outer retina. Genetic discovery can help elucidate the pathways through which choroidal features influence disease risk. Our meta-analysis of genome-wide association studies (n= 78,682 participants) identified 30 genomic regions, including 20 novel loci, associated with choroidal thickness. Findings suggest inflammatory and vascular processes drive choroidal thickness, with overlapping mechanisms shared with refractive error. Genome-wide independently significant SNPs accounted for 18.7% of the genetic variance in choroidal thickness. Mendelian randomisation analyses showed a causal effect of age-related macular degeneration on choroidal thickness, and suggest a bidirectional causal effect between choroidal thickness and primary angle-closure glaucoma. These findings provide insight into the shared genetic architecture and biological pathways linking choroidal thickness and related diseases.

Early life nutrition is associated with child behaviour; however, the interplay with genetic vulnerability is understudied. We hypothesised that psychiatric genetic risk interacted with early nutrition to predict behavioural problems in childhood and adolescence. The Raine Study participants with genetic information aged 2–17 were repeatedly evaluated with the child behaviour checklist total problems score (CBCLTOT). Breastfeeding duration was recalled at age 1, 2 and 3 follow-up, and toddler diet derived by an age-1 24-h maternal recall (EAT1, scale 0–70, SD 10, higher scores proxying healthy diet). We derived polygenic scores (PGS) impacting general psychopathology: attention-deficit hyperactivity disorder (ADHD), depression, chronic multisite pain (CMSP), total behaviour problems and birthweight. In confounder-adjusted mixed-effects models of CBCLTOT throughout follow-up we examined nutrition-by-PGS interactions. In 1393 participants, a borderline signal suggests that 1 month longer breastfeeding reduces CBCLTOT by −0.108 (95

Interpregnancy interval (IPI) has been reported to be associated with the risk of pregnancy complications. Short IPIs have been associated with higher risks of preterm birth, small for gestational age, low birthweight, fetal growth restriction, and perinatal mortality. However, there is limited information on how these associations differ according to the developmental status of a country. This review is therefore designed to examine the impact of the developmental status of a country on the relationship between IPI and perinatal complications. Studies will be identified through a comprehensive search of MEDLINE, EMBASE, Global Health, LILACS, and African Index Medicus databases, using key terms including “interpregnancy interval”, “birth interval”, “preterm birth”, “small for gestational age”, “fetal growth restriction”, and “perinatal mortality”. Studies to be included will be screened for data reporting on IPI and relevant outcomes. The study population will consist of women with two or more singleton births. The exposure of interest is short IPI, categorised as (1) < 24 monthsmonths; ≤ 18 months; and ≤ 12 months between the birth of a child and conception of the next pregnancy. These exposure groups will be compared against the World Health Organisation recommendation of an IPI of at least 24 months. Co-primary outcomes are preterm birth, small for gestational age, fetal growth restriction, low birthweight, and perinatal mortality. The developmental status of study populations will be categorised according to the World Bank income-based country classifications for low-, middle-, and high-income countries. Studies will be included if they have an observational design and excluded if they are systematic reviews with no new data. All studies will be screened, data extracted, and bias assessed by two independent authors, with all discrepancies being resolved by consensus or the advice of a third author. If studies have a low heterogeneity (I2 < 50

Adolescent depression is a heritable psychiatric condition with rising global prevalence and severe long-term outcomes, yet its biological underpinnings remain poorly understood. We conducted the first genome-wide association study of adolescent-onset depression, comprising 102,428 cases (diagnosis or clinical symptom thresholds) and 286,911 controls, including diverse ancestries. Cross-ancestry meta-analysis identified 52 independent variants across 17 loci; European-only analysis found 61 variants at 29 loci, with a SNP-based heritability of 9.8%. Comparative analyses revealed two genes unique to adolescent-onset versus lifetime depression, enriched in neuronal subtypes, and two genes as potential drug repurposing targets. Polygenic scores were associated with adolescent-onset depression across ancestries, persistent depression trajectories, more severe outcomes, as well as reduced cortical volume, surface area and white matter integrity. Genetic correlation and Mendelian randomisation analyses support shared genetic liability and causal links with early puberty and modifiable health and behavioural risk factors. These findings uncover novel genetic loci and refine biological pathways underlying adolescent-onset depression, revealing age-specific mechanisms and early intervention opportunities.

We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHDSYMP). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHDOVERALL). ADHDSYMP returned no genome-wide significant variants. We show that the combined ADHDOVERALL GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (rg < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHDOVERALL outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

Background:Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. Results:The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusions:Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Background Mitochondria are organelles required for bioenergetic homeostasis, providing energy in the form of ATP to support cellular function, growth, and proliferation. Mitochondria synthesise ATP using the electron transport chain (ETC) to produce an electrochemical gradient that facilitates the conversion of ADP to ATP by ATP synthase. Mitochondrial function is governed by an intricate bidirectional relationship between the mitochondrial genome encoding 1-2% of proteins and the nuclear genome which encodes 98-99% of mitochondrial proteins. Pregnancy creates a unique environment whereby the mitochondrial genome of the placenta is maternally inherited, while the nuclear genome is comprised of both maternal and paternal contributions. Thus, mitochondrial structure and function are largely dependent on the adaptability of mitochondria to conform to the new mixed nuclear genome. In pregnancy, fetal growth restriction (FGR) is characterised by poor placental development, underlying trophoblast insufficiencies, and is associated with mitochondrial dysfunction within the placenta, although the mechanisms which underpin these changes remain unclear. This study investigated if mitochondrial dysfunction in FGR is programmed by genetic incompatibility arising from single nucleotide polymorphisms (SNPs). Methods and findings We performed a targeted meta-analysis of over 100 genome wide association studies within the early growth genetics (EGG) consortium, assessing 289 genes encoding mitochondrial function across the ETC and ATP synthase. This study identified 37 SNPs across 32 genes associated with low birthweight. Sanger sequencing was performed to validate the presence of 10 SNPs of interest located within the nuclear genome in a cohort of fetal growth restricted placentas. Of the 10 SNPs assessed we confirmed the presence of 6 in FGR, and identified an additional previously unidentified SNP, and detected 3 nucleotide deletions across numerous components of the electron transport chain. This analysis identified 5 mutations within genes that encode complex I. Subsequent analysis of the gene and proteins that correspond to complex I mutations was performed using PCR, proteomics, and western blotting. Notably, we identified significant downregulation of NDUFA6 at the gene and protein level in FGR, lower protein levels of NDUFS3 and NDUFS6, and confirmed the largest log2 fold change identified in NDUFS6 by western blot. Subsequent investigation of mitochondrial respiratory capacity identified decreased ATP-linked respiration in FGR using Seahorse XF Analysis. Conclusion Our results identify that there is an inheritable contribution of SNPs within the maternal and paternal nuclear genome in fetal growth restriction. These SNPs alter gene expression and protein abundance of mitochondrial complex I components, impacting structural assembly and subsequent bioenergetic function within the placenta. Collectively these findings suggest that SNPs that affect mitochondrial assembly and function are associated with low birthweight and fetal growth restriction. ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, GNT2026065

Social behaviour is a heritable, context-dependent trait that changes across social settings and development, influencing wellbeing and mental health. We present the first genome-wide meta-regression study of social behaviour from infancy to early adulthood, leveraging 491,246 repeat measures of low prosocial behaviour and peer/social difficulties in European-ancestry cohorts (Neff=121,777, Nind=73,321). We modelled heterogeneity in genetic effects across social domains, informants, and ages (2–29 years), capturing social context through genomic influences. Six loci were identified, including variation within CADM2 ( p =2.51x10-[9][1]). The SNP-based heritability was modest (2–7%), and the genetic architecture of social behaviour multidimensional. Polygenic scores demonstrated predictability and accuracy in independent European-ancestry cohorts and, partially, in African-ancestry cohorts (Nind=16,305). Genetic correlations with later-life and mental health outcomes showed context-dependent patterns. Modelling predicted onsets of associations with social behaviour revealed distinct profiles, as observed for autism, ADHD, depression and schizophrenia, highlighting novel opportunities to genetically proxy developmental trajectories. ### Competing Interest Statement H.L. reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. H.L. is editor-in-chief of JCPP Advances. J.A.R-Q. was on the speakers bureau and/or acted as a consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubio, Uriach, Technofarma and Raffo in the last 3 years. J.A.R-Q. also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubio, Takeda, Bial and Medice. The Department of Psychiatry, chaired by J.A.R-Q., received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubio. E.D.R. has served as a speaker for Shire Sweden AB, a Takeda Pharmaceutical Company, outside of this work. S.B. discloses that he has in the last 3 years acted as a consultant or lecturer for Medice, Takeda, and LinusBio. S.B. receives royalties for textbooks and diagnostic tools from Hogrefe, UTB, Ernst Reinhardt, Kohlhammer, and Liber. S.B. is a partner in NeuroSupportSolutions International AB. All other authors declare no conflict of interest. R2D2-MH, Horizon Europe, 101057385 R2D2-MH, UK Research and Innovation (UKRI), under the UK government’s Horizon Europe funding guarantee, 10039383 R2D2-MH, Swiss State Secretariat for Education, Research and Innovation (SERI), contract number: 22.00277 ZonMW, TOP 40–00812–98–11010 Horizon Europe Research and Innovation Programme, FAMILY, 101057529, HappyMums, 101057390 European Research Council, TEMPO, 101039672 Dutch Ministry of Education, Culture, and Science and the Netherlands Organisation for Scientific Research, 024.001.003, Consortium on Individual Development, NWO-VICI, NWO-ZonMW: 016.VICI.170.200 Horizon 2020 research and innovation program, Contract grant no. 633595, DynaHealth, LongITools, 874739, EarlyCause, 848158 China Scholarship Council, 201706990036 Max Planck Society Radboud University Donders RSF 2025 Ter Meulen Grant of the Royal Netherlands Academy of Arts and Sciences (KNAW) Strategic Research Council (SRC) established within the Academy of Finland, decision no. 352700 Instituto de Salud Carlos III, co-funded by the European Union Fund (Fondo Social Europeo Plus, FSE+), contract no. CP22/00026 Research Council of Norway (RCN), #274611, #336085, #274611, #274611, #288083, #336078 South-Eastern Norway Regional Health Authority (HSO), #2020022, #2018059, #2021045 MRC Integrative Epidemiology Unit, University of Bristol, Medical Research Council, University of Bristol, MC\_UU\_00032/1 European Union, 101045526, 818425 University of Oulu, Academy of Finland Profi6, decision number AF 336449 Research Council of Finland, STAGE [Grant N° 101137146], IHEN [Grant N° 101137317], OBELISK Grant [N° 101080465], OBCT [Grant N° 101080250], TRIGGER [Grant N° 101057739] Research Council of Finland, 356888 MRC Centre for Environment and Health, Medical Research Council, UK, MR/S019669/1 Simons Foundation, 724306 Sir Henry Wellcome Postdoctoral Fellowship, 213514/Z/18/Z Ministry of Science, Technology and Innovation, https://ror.org/012s3r374, State Research Agency grant RYC2022-038136-I, European Union FSE+, State Research Agency grant PID2022-143106OA-I00, European Union FEDER William H. Gates Sr. Fellowship from the Alzheimer’s Disease Data Initiative UK Medical Research Council, Grant Nos. MR/V012878/1 and previously MR/M021475/1 US National Institutes of Health, AG046938 European Research Council under the European Union's Seventh Framework Programme, FP7/2007-2013, grant agreement n° 602768 UK Research and Innovation, 10063472 EU-AIMS (European Autism Interventions) & AIMS-2-TRIALS, European Union FP7 & Horizon2020 Programmes, the European Federation of Pharmaceutical Industries and Associations (EFPIA), AUTISM SPEAKS, Autistica, SFARI,, Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, Horizon2020 supported programme CANDY Grant No. 847818 [1]: #ref-9

BACKGROUND:Multiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene-environment interactions (G × E) to improve understanding of the pathophysiology. METHODS:We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. RESULTS:The discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p < 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure × rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction = 0.91 [0.83-0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction = 0.84 [0.75-0.94] p = 0.003), but replication analysis was under-powered (ORinteraction = 1.09 [0.82-1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSION:Interaction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G × E studied here implies only weak effects are likely to occur.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at P interaction <5e−8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score ( P interaction =4e−8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg ( P interaction =9.4e−7) and 0.20±0.06 mm Hg ( P interaction =0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants ( P =4e−273) and cis-DNA methylation quantitative trait loci variants ( P =1e−300). Although the closest gene for rs117878928 is MTHFS , the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

AbstractBackgroundThe longitudinal impact of fetal growth on attention problems in males and females is unclear. This study aims to evaluate the impact of fetal growth assessed by neonatal anthropometry throughout childhood and adolescence in males and females separately.MethodsWe compared neonatal anthropometry (birth weight (BW), head circumference (HC), proportion of optimal birthweight (POBW)) and asymmetry (head‐to‐abdominal circumference ratio (HC/AC) and ponderal index (PI)) at birth with parental assessment of the child behavior checklist attention‐problem syndrome (CBCL‐AP) raw score measured at ages five, eight, 10, 14 and 17. We used univariable and multivariable linear mixed‐effects modeling. Sensitivity analyses included excluding pre‐term births, teacher ratings and treating the CBCL‐AP as an ordinal variable.ResultsIn males, a 1‐SD lower BW, increased CBCL‐AP by 0.234 (95%CI [−0.422, −0.0497]). In males, a 1‐SD lower HC increased CBCL‐AP by 0.316 (95%CI [0.495, 0.133]). In males, there was a U‐shaped relationship between HC/AC and CBCL‐AP throughout childhood and adolescence; a curvilinear relationship was observed between POBW and CBCL‐AP. In females, a 1 SD lower HC increased CBCL‐AP 0.424 (95%CI [0.726, 0.133]), but every increased year of age reduced the effect by 0.027 (95% CI: 0.006–0.05). In females, there was no clear relationship between BW, POBW or HC/AC and CBCL‐AP. In males and females, PI was not significantly associated with CBCL‐AP. The exclusion of pre‐term births and analysis of teacher‐rated attention problems was consistent with the primary results.ConclusionsUsing a longitudinal design, our study suggests a male vulnerability to attention problems throughout childhood and adolescence from neonatal anthropometry. The relationships in females appear to be limited to childhood.