Genetic risk of type 2 diabetes modifies the association between lifestyle and glycemic health at 5 years postpartum among high-risk women.

INTRODUCTION: Lifestyle interventions are effective in preventing type 2 diabetes, but genetic background may influence the individual response. In the Finnish gestational diabetes prevention study, RADIEL, lifestyle intervention during pregnancy and first postpartum year was effective in preventing gestational diabetes (GDM) and postpartum glycemic abnormalities only among women at highest genetic risk of type 2 diabetes. This study aimed to assess whether still 5 years postpartum the genetic risk modifies the association between lifestyle and glycemic health. RESEARCH DESIGN AND METHODS: The RADIEL study (randomized controlled trial) aimed to prevent GDM with a lifestyle intervention among high-risk women (body mass index ≥30 kg/m2 and/or prior GDM). The follow-up study 5 years postpartum included anthropometric measurements, laboratory assessments, device-measured physical activity (PA), and questionnaires. A Healthy Lifestyle Score (HLS) indicated adherence to lifestyle goals (PA, diet, smoking) and a polygenic risk score (PRS) based on 50 type 2 diabetes risk alleles depicted the genetic risk. RESULTS: Altogether 314 women provided genetic and glycemic data 5 years postpartum. The PRS for type 2 diabetes was not associated with glycemic abnormalities, nor was HLS in the total study sample. There was, however, an interaction between HLS and type 2 diabetes PRS on glycemic abnormalities (p=0.03). When assessing the association between HLS and glycemic abnormalities in PRS tertiles, HLS was associated with reduced risk of glycemic abnormalities only among women at the highest genetic risk (p=0.008). CONCLUSIONS: These results extend our previous findings from pregnancy and first postpartum year demonstrating that still at 5 years postpartum, healthy lifestyle is associated with a lower risk of prediabetes/diabetes only among women at the highest genetic risk of type 2 diabetes.

Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis.

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women.

Background: To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus. Methods: This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity. Results: Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes. Conclusion: hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Affect dimensions and variability during major depressive episodes: Ecological momentary assessment of unipolar, bipolar, and borderline patients and healthy controls.

Differentiating major depressive episodes (MDEs) of major depressive disorder (MDD), bipolar disorder (MDE/BD) and the MDEs comorbid with borderline personality disorder (MDE/BPD) is crucial for appropriate treatment, and knowledge of phenomenological differences may aid this. However, studies comparing affect experiences of these three patient groups and healthy subjects are scarce. In our study, participants (N = 114), including patients with MDD (n = 34), MDE/BD (n = 27), and MDE/BPD (n = 24), and healthy controls (HC, n = 29) responded to ecological momentary assessment (EMA) with ten circumplex model affect items ten times daily for seven days (7709 recordings). Explorative factor analysis resulted in two affect dimensions. The positive dimension included active, excited, cheerful (high arousal), and content (low arousal) affects, and the negative dimension irritated, angry, and nervous (high arousal) affects. Relative to HC, patients reported 3.5-fold negative affects (mean MDD 1.36 (SD 0.92), MDE/BD 1.43 (0.76), MDE/BPD 1.81 (0.95) vs. HC 0.44 (0.49) (p < 0.01)) but 0.5-fold positive affects (2.01 (0.90), 1.95 (0.89), 2.24 (1.03), vs. 3.2 (0.95), respectively (p < 0.01)). We used multilevel modelling. Negative-affect within-individual stability was lowest in MDE/BPD and highest in MDD. Negative affect predicted concurrent positive affect more in MDE/BPD than in MDD. Moderate size of subcohorts and no inpatients were limitations. Despite apparently similar MDEs, affective experiences may differ between BPD, BD, and MDD patients. Clinical subgroups of patients with depression may vary in affective instability and concurrent presence of negative and positive affects during depression.

Pet and owner personality and mental wellbeing associate with attachment to cats and dogs.

Human-pet attachment can impact the life of both parties, and the identification of underlying characteristics related to attachment style can improve human-pet relationships. We employed structural equation modeling (SEM) to explore associations between human, dog, and cat personalities, owner mental well-being, unwanted pet behavior, and attachment styles in a sample of 2,724 Finnish pet owners (92% women) and their 2,545 dogs and 788 cats. Our findings reveal that owner neuroticism and poor mental well-being are linked to anxious pet attachment in both dog and cat owners. Pet characteristics, such as unwanted behavior and lower human sociability are associated with avoidant attachment style. Overall, this study highlights the significance of individual traits in both pets and owners contributing to insecure attachment styles and underscores the potential to enhance the well-being of both pets and their owners through a deeper understanding of these traits.

Maternal social support during and after pregnancy and child cognitive ability: examining timing effects in two cohorts.

BACKGROUND: Maternal anxiety, depression, and stress during and after pregnancy are negatively associated with child cognitive development. However, the contribution of positive maternal experiences, such as social support, to child cognitive development has received less attention. Furthermore, how maternal experience of social support during specific developmental periods impacts child cognitive development is largely unknown. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 5784) and the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study (PREDO; n = 420), we investigated the associations between maternal perceived social support during and after pregnancy and child's general cognitive ability at 8 years of age, assessed with the Wechsler Intelligence Scale for Children (WISC). Bayesian relevant life course modeling was used to investigate timing effects of maternal social support on child cognitive ability. RESULTS: In both cohorts, higher maternal perceived social support during pregnancy was associated with higher performance on the WISC, independent of sociodemographic factors and concurrent maternal symptoms of depression and anxiety. In ALSPAC, pregnancy emerged as a sensitive period for the effects of perceived social support on child cognitive ability, with a stronger effect of social support during pregnancy than after pregnancy on child cognitive ability. CONCLUSIONS: Our findings, supported from two prospective longitudinal cohorts, suggest a distinct role of maternal perceived social support during pregnancy for cognitive development in children. Our study suggests that interventions aimed at increasing maternal social support during pregnancy may be an important strategy for promoting maternal and child well-being.

Independent Prediction of Child Psychiatric Symptoms by Maternal Mental Health and Child Polygenic Risk Scores.

OBJECTIVE: Prenatal maternal symptoms of depression and anxiety are associated with an increased risk for child socioemotional and behavioral difficulties, supporting the fetal origins of mental health hypothesis. However, to date, studies have not considered specific genomic risk as a possible confound. METHOD: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 5,546) was used to test if child polygenic risk score for attention-deficit/hyperactivity disorder (ADHD), schizophrenia, or depression confounds or modifies the impact of prenatal maternal depression and anxiety on child internalizing, externalizing, and total emotional/behavioral symptoms from age 4 to 16 years. Longitudinal child and adolescent symptom data were analyzed in the ALSPAC cohort using generalized estimating equations. Replication analyses were done in an independent cohort (Prevention of Preeclampsia and Intrauterine Growth Restriction [PREDO] cohort; n = 514) from Finland, which provided complementary measures of maternal mental health and child psychiatric symptoms. RESULTS: Maternal depression and anxiety and child polygenic risk scores independently and additively predicted behavioral and emotional symptoms from childhood through mid-adolescence. There was a robust prediction of child and adolescent symptoms from both prenatal maternal depression (generalized estimating equation estimate = 0.093, 95% CI 0.065-0.121, p = 2.66 × 10-10) and anxiety (generalized estimating equation estimate = 0.065, 95% CI 0.037-0.093, p = 1.62 × 10-5) after adjusting for child genomic risk for mental disorders. There was a similar independent effect of maternal depression (B = 0.156, 95% CI 0.066-0.246, p = .001) on child symptoms in the PREDO cohort. Genetically informed sensitivity analyses suggest that shared genetic risk only partially explains the reported association between prenatal maternal depression and offspring mental health. CONCLUSION: These findings highlight the genomic contribution to the fetal origins of mental health hypothesis and further evidence that prenatal maternal depression and anxiety are robust in utero risks for child and adolescent psychiatric symptoms.

Positive maternal mental health during pregnancy and psychiatric problems in children from early childhood to late childhood.

Negative maternal mental health during pregnancy increases the risk of psychiatric problems in children, but research on the potential benefits of positive maternal mental health during pregnancy is scarce. We investigated associations between positive maternal mental health composite score, based on reports of maternal positive affect, curiosity, and social support during pregnancy, and children's psychiatric problems (Child Behavior Checklist) at ages 1.9-5.9 and 7.1-12.1 years among 2636 mother-child dyads of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study. For each standard deviation higher positive maternal mental health score during pregnancy, total psychiatric problems were 1.37 (95% confidence interval (CI) -1.79,-0.95) t-scores lower in early childhood and 1.75 (95% CI -2.24,-1.26) t-scores lower in late childhood. These associations were independent of covariates and of negative maternal mental health. Total psychiatric problems remained stably lower from early childhood to late childhood in children of mothers with higher positive mental health during pregnancy, whereas they increased in children of mothers with lower positive mental health. Positive maternal mental health in child's late childhood partially mediated the effects of positive maternal mental health during pregnancy on children's psychiatric problems. Supporting positive maternal mental health may benefit mothers and children.

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity.

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10-307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10-114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50-80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its' association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

Delayed bedtime on non-school days associates with higher weight and waist circumference in children: Cross-sectional and longitudinal analyses with Mendelian randomisation.

Sleep duration has been linked with obesity in population-based studies. Less is known about bedtimes and, especially, if discrepancy between bedtimes on school and non-school days associate with adiposity in children. The associations of self-reported bedtimes with the body mass index z-score (BMIz) and waist-to-height ratio (WtHr) were examined among children with a mean (SD) age of 11.2 (0.85) years in cross-sectional (n = 10,245) and longitudinal (n = 5085) study settings. The causal relationship of whether BMIz contributes to bedtimes, was further examined in a subset of 1064 participants by exploiting Mendelian randomisation (MR). After adjusting for sleep duration and other confounders, every 0.5 h later bedtime on non-school nights and a delay in bedtime in non-school nights compared with school nights associated with 0.048 (95% CI 0.027; 0.069) and 0.08 (95% CI 0.056; 0.105) higher BMIz as well as 0.001 (95% CI 0; 0.002) and 0.004 (95% CI 0.003; 0.005) with higher WtHr, respectively. Moreover, every 0.5-h delay in bedtime in non-school nights compared with school nights associated with 0.001 (95% CI 0; 0.002) greater increase in WtHr in the 2.5 years follow-up. Thus, a 2-h delay in bedtime at the age of 11 years corresponds with a 0.6 cm increase in waist circumference. The MR analysis did not indicate an opposite causal relationship: higher BMIz was not causing delayed bedtimes. Later bedtime on non-school days and discrepancy in bedtimes associated with increased BMIz and WtHr, while longitudinally these predicted higher WtHr, independently of sleep duration. Promoting early bedtimes, especially on weekends, should be considered in obesity prevention among school-aged children.

DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium.

The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10-8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.

Maternal exposure to childhood maltreatment and mental and behavioral disorders in children.

Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252) of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort study completed the Childhood Trauma Questionnaire and reported on their education and their 7.0-12.1-year-old children's psychiatric symptoms using the Strengths and Difficulties Questionnaire. We identified lifetime mental and behavioral disorder diagnoses for the mothers and diagnoses for their children from birth (2006-2010) until 8.4-12.8 years (12/31/2018) from Care Register for Health Care. We found that maternal exposure to childhood abuse, but not neglect, was associated with higher hazards of mental and behavioral disorders (hazard ratio 1.20, 95% confidence interval 1.06-1.37) in children. These associations were partially mediated by maternal mental and behavioral disorders and education (proportion of effect size mediated: 23.8% and 15.1%, respectively), which together with maternal exposure to childhood abuse added to the hazard of mental and behavioral disorders in children. Similar associations were found for maternal exposure to childhood abuse and neglect with psychiatric symptoms in children. To conclude, maternal exposure to childhood maltreatment is associated with mental and behavioral disorders and psychiatric symptoms in children. Our findings call for interventions to prevent intergenerational transmission.

Positive maternal mental health during pregnancy and mental and behavioral disorders in children: A prospective pregnancy cohort study.

BACKGROUND: The role of positive maternal mental health during pregnancy in child mental health remains largely unknown. We investigated whether positive maternal mental health during pregnancy is associated with lower hazards of mental and behavioral disorders in children and mitigates the adverse effects of negative maternal mental health. METHODS: Among 3,378 mother-child dyads of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study, mothers reported their positive mental health biweekly throughout pregnancy with the Positive and Negative Affect Schedule, the Spielberger State Anxiety Inventory Curiosity scale, and a visual analogue scale for social support, and negative mental health with the Center for Epidemiologic Studies Depression Scale. We extracted data on their mental and behavioral disorder diagnoses from a nationwide medical register. This register provided data on their children's mental and behavioral disorder diagnoses as well, from birth until 8.4-12.8 (Median = 10.2, Interquartile Range 9.7-10.8) years of age. RESULTS: A positive maternal mental health composite score during pregnancy was associated with a lower hazard of any mental and behavioral disorder among all children [Hazard Ratio (HR) = 0.79, 95% Confidence Interval (CI) 0.71 - 0.87] and among children of mothers experiencing clinically relevant depressive symptoms during pregnancy [HR = 0.80, 95%CI 0.64 - 1.00] and/or mental and behavioral disorders before or during pregnancy [HR = 0.69, 95%CI 0.55-0.86]. These associations were independent of covariates. CONCLUSIONS: Children whose mothers had more positive mental health during pregnancy were less likely to develop mental and behavioral disorders. Protective effects were seen also among children of mothers facing mental health adversities before or during pregnancy.

Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing.

Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22−13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth.

Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires: lessons from a pilot study within FinnGen.

OBJECTIVES: To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform. DESIGN: Biobank-based recontacting pilot study. SETTING: Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021. PARTICIPANTS: All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s). OUTCOME MEASURES: The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies. RESULTS: The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18-69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92. CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.

Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.

Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children.

Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4-12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7-65.6%, and hence the predictive significance of the model, and mediated 60.8-75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolomic perturbations during pregnancy are associated with a higher risk of mental and behavioral disorders in children. These findings may allow identifying metabolomic targets for personalized interventions.