A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts.

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (in DAOA) and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits.

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Visual memory and alcohol use in a middle-aged birth cohort.

Light and moderate alcohol use has been reported to be associated with both impaired and enhanced cognition. The purpose of this study was to explore whether there was a linear relationship between visual memory and alcohol consumption in males and females in a large middle-aged birth cohort population in cross-sectional and longitudinal settings. Data were collected from 5585 participants completing 31-year (1997-1998) and 46-year (2012-2014) follow-ups including Paired Associate Learning (PAL) test at 46-years follow-up. The participants were originally from 12,231 study population of the Northern Finland Birth Cohort 1966 (NFBC1966). The PAL test was conducted to assess visual memory. Reported alcohol use was measured as total daily use of alcohol, beer, wine, and spirits converted into grams and as frequency and amount of use of beer, wine, and spirits. The total daily alcohol use was not associated with reduced visual memory. The frequency of use of beer and wine in males was associated with better visual memory in cross-sectional and longitudinal settings. Using six or more servings of spirits was associated with worse visual memory in males in cross-sectional and longitudinal settings. Using six or more servings of spirits was associated with worse visual memory in males in cross-sectional and longitudinal setting. The study suggested a lack of a linear association between drinking and visual memory in the middle-aged population.

Effect of Aerobic Exercise and Time-Restricted Feeding on Metabolic Markers and Circadian Rhythm in Mice Fed with the High-Fat Diet.

SCOPE: Diet and exercise are significant players in obesity and metabolic diseases. Time-restricted feeding (tRF) has been shown to improve metabolic responses by regulating circadian clocks but whether it acts synergically with exercise remains unknown. It is hypothesized that forced exercise alone or combined with tRF alleviates obesity and its metabolic complications. METHODS AND RESULTS: Male C57bl6 mice are fed with high-fat or a control diet for 12 weeks either ad libitum or tRF for 10 h during their active period. High-fat diet (HFD)-fed mice are divided into exercise (treadmill for 1 h at 12 m min-1 alternate days for 9 weeks and 16 m min-1 daily for the following 3 weeks) and non-exercise groups. tRF and tRF-Ex significantly decreased body weight, food intake, and plasma lipids, and improved glucose tolerance. However, exercise reduced only body weight and plasma lipids. tRF and tRF-Ex significantly downregulated Fasn, Hmgcr, and Srebp1c, while exercise only Hmgcr. HFD feeding disrupted clock genes, but exercise, tRF, and tRF-Ex coordinated the circadian clock genes Bmal1, Per2, and Rev-Erbα in the liver, adipose tissue, and skeletal muscles. CONCLUSION: HFD feeding disrupted clock genes in the peripheral organs while exercise, tRF, and their combination restored clock genes and improved metabolic consequences induced by high-fat diet feeding.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Developmental origins of psycho-cardiometabolic multimorbidity in adolescence and their underlying pathways through methylation markers: a two-cohort study.

Understanding the biological mechanisms behind multimorbidity patterns in adolescence is important as they may act as intermediary risk factor for long-term health. We aimed to explore relationship between prenatal exposures and adolescent's psycho-cardiometabolic intermediary traits mediated through epigenetic biomarkers, using structural equation modeling (SEM). We used data from mother-child dyads from pregnancy and adolescents at 16-17 years from two prospective cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) and Raine Study from Australia. Factor analysis was applied to generate two different latent factor structures: (a) prenatal exposures and (b) adolescence psycho-cardiometabolic intermediary traits. Furthermore, three types of epigenetic biomarkers were included: (1) DNA methylation score for maternal smoking during pregnancy (DNAmMSS), (2) DNAm age estimate PhenoAge and (3) DNAm estimate for telomere length (DNAmTL). Similar factor structure was observed between both cohorts yielding three prenatal factors, namely BMI (Body Mass Index), SOP (Socio-Obstetric-Profile), and Lifestyle, and four adolescent factors: Anthropometric, Insulin-Triglycerides, Blood Pressure, and Mental health. In the SEM pathways, stronger direct effects of F1prenatal-BMI (NFBC1986 = ß: 0.27; Raine = ß: 0.39) and F2prenatal-SOP (ß: -0.11) factors were observed on adolescent psycho-cardiometabolic multimorbidity. We observed an indirect effect of prenatal latent factors through epigenetic markers on a psycho-cardiometabolic multimorbidity factor in Raine study (P < 0.05). The present study exemplifies an evidence-based approach in two different birth cohorts to demonstrate similar composite structure of prenatal exposures and psycho-cardiometabolic traits (despite cultural, social, and genetic differences) and a common plausible pathway between them through underlying epigenetic markers.

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10-7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10-4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

Clinical and biochemical associations of urinary metabolites: quantitative epidemiological approach on renal-cardiometabolic biomarkers.

BACKGROUND: Urinary metabolomics has demonstrated considerable potential to assess kidney function and its metabolic corollaries in health and disease. However, applications in epidemiology remain sparse due to technical challenges. METHODS: We added 17 metabolites to an open-access urinary nuclear magnetic resonance metabolomics platform, extending the panel to 61 metabolites (n = 994). We also introduced automated quantification for 11 metabolites, extending the panel to 12 metabolites (+creatinine). Epidemiological associations between these 12 metabolites and 49 clinical measures were studied in three independent cohorts (up to 5989 participants). Detailed regression analyses with various confounding factors are presented for body mass index (BMI) and smoking. RESULTS: Sex-specific population reference concentrations and distributions are provided for 61 urinary metabolites (419 men and 575 women), together with methodological intra-assay metabolite variations as well as the biological intra-individual and epidemiological population variations. For the 12 metabolites, 362 associations were found. These are mostly novel and reflect potential molecular proxies to estimate kidney function, as the associations cannot be simply explained by estimated glomerular filtration rate. Unspecific renal excretion results in leakage of amino acids (and glucose) to urine in all individuals. Seven urinary metabolites associated with smoking, providing questionnaire-independent proxy measures of smoking status in epidemiological studies. Common confounders did not affect metabolite associations with smoking, but insulin had a clear effect on most associations with BMI, including strong effects on 2-hydroxyisobutyrate, valine, alanine, trigonelline and hippurate. CONCLUSIONS: Urinary metabolomics provides new insight on kidney function and related biomarkers on the renal-cardiometabolic system, supporting large-scale applications in epidemiology.

Early life exposures contributing to accelerated lung function decline in adulthood - a follow-up study of 11,000 adults from the general population.

Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements. Methods: Participants (20-68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991-2013 and 1997-2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV1) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV1, FVC and height at baseline, accounting for personal smoking. Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV1 2.6 ml/year; 0.9, 4.4) (FEV1/FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found. Interpretation: Mothers' smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV1 and FVC later in life comparable to smoking 10 pack-years. Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya.

NMR metabolomic modelling of age and lifespan: a multi-cohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. 98 metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈ 31,000 individuals, age range 24-86 years). We used non-linear and penalised regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with ageing risk factors and phenotypes. Within the UK Biobank (N≈ 102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, chronic obstructive pulmonary disease) and all-cause mortality. Cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47-0.65 in the training set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with chronological age were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06 / metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Investigating the relationship between non-occupational pesticide exposure and metabolomic biomarkers.

The relationship between pesticide exposures and metabolomics biomarkers is not well understood. We examined the changes in the serum metabolome (early biomarkers) and the metabolic pathways associated with various pesticide exposure scenarios (OPE: overall exposure, PEM: exposure in months, PEY: exposure in years, and PEU: reported specific pesticides use) using data from the Northern Finland Birth Cohort 1966 31-year cross-sectional examination. We utilized questionnaire data on pesticide exposures and serum samples for nuclear magnetic resonance (NMR)-based metabolomics analyses. For exposures and metabolites associations, participants size varied between 2,361 and 5,035. To investigate associations between metabolomics biomarkers and exposure to pesticide scenarios compared to those who reported no exposures multivariable regression analyses stratified by sex and adjustment with covariates (season of pesticide use, socioeconomic position (SEP), alcohol consumption, BMI, and latitude of residence) were performed. Multiple testing by Benjamini-Hochberg false discovery rate (FDR) correction applied. Pesticide exposures differed by sex, season of pesticide use, alcohol, SEP, latitude of residence. Our results showed that all pesticide exposure scenarios were negatively associated with decreased HDL concentrations across all lipoprotein subclasses in women. OPE, PEY, and PEU were associated with decreased branched-chain amino acid concentrations in men and decreased albumin concentrations in women. OPE, PEY and PEU were also associated with changes in glycolysis metabolites and ketone bodies in both sexes. Specific pesticides exposure was negatively associated with sphingolipids and inflammatory biomarkers in men. In women, OPE, PEM, and PEU were associated with decreased apolipoprotein A1 and increased apolipoprotein B/apolipoprotein A1 ratio. Our findings suggest that identification of early biomarkers of disease risk related to pesticide exposures can inform strategies to reduce exposure and investigate causal pathways. Women may be more susceptible to non-occupational pesticide exposures when compared to men, and future sex-specific studies are warranted.

Epigenome-Wide Meta-analysis Reveals Associations Between Dietary Glycemic Index and Glycemic Load and DNA Methylation in Children and Adolescents of Different Body Sizes.

OBJECTIVE: Dietary glycemic index (GI) and glycemic load (GL) are associated with cardiometabolic health in children and adolescents, with potential distinct effects in people with increased BMI. DNA methylation (DNAm) may mediate these effects. Thus, we conducted meta-analyses of epigenome-wide association studies (EWAS) between dietary GI and GL and blood DNAm of children and adolescents. RESEARCH DESIGN AND METHODS: We calculated dietary GI and GL and performed EWAS in children and adolescents (age range: 4.5-17 years) from six cohorts (N = 1,187). We performed stratified analyses of participants with normal weight (n = 801) or overweight or obesity (n = 386). We performed look-ups for the identified cytosine-phosphate-guanine (CpG) sites (false discovery rate [FDR] <0.05) with tissue-specific gene expression of 832 blood and 223 subcutaneous adipose tissue samples from children and adolescents. RESULTS: Dietary GL was positively associated with DNAm of cg20274553 (FDR <0.05), annotated to WDR27. Several CpGs were identified in the normal-weight (GI: 85; GL: 17) and overweight or obese (GI: 136; GL: 298; FDR <0.05) strata, and none overlapped between strata. In participants with overweight or obesity, identified CpGs were related to RNA expression of genes associated with impaired metabolism (e.g., FRAT1, CSF3). CONCLUSIONS: We identified 537 associations between dietary GI and GL and blood DNAm, mainly in children and adolescents with overweight or obesity. High-GI and/or -GL diets may influence epigenetic gene regulation and thereby promote metabolic derangements in young people with increased BMI.

Associations of adolescents' diet and meal patterns with school performance in the Northern Finland Birth Cohort 1986: A Mendelian randomisation study.

BACKGROUND: Several observational studies indicate that dietary habits in children and adolescents are associated with school performance. These associations are heavily confounded by socio-economic characteristics, such as household income and parents' educational attainment, amongst other factors. The objective of this study was to explore the association between diet and school performance in adolescents from the Northern Finland Birth Cohort 1986 (NFBC1986). METHODS: Dietary and school performance data were collected using self-reported questionnaires from adolescents in the NFBC1986 cross-sectional, 16-year follow-up study. In this work we derived exploratory factors for the dietary variables, frequency of skipping main meals and school performance variables, performed genome-wide association studies (GWAS) against these factors to obtain genetic association data and conducted one-sample and two-sample Mendelian randomisation (MR) analyses using individual level data for up to 9220 adolescents in NFBC1986 and GWAS results from external cohorts. We report observational and MR effects of diet on school performance and cognition-related phenotypes. RESULTS: The observational study and the one-sample Mendelian randomisation analysis showed that high fat, salt and sugar (HFSS) consumption was associated with poor school performance in general/science subjects (-0.080, -0.128 to -0.033) and staple food consumption with better school performance in general/science subjects (0.071, 0.024 to 0.119) and physical education (0.065, 0.021 to 0.110). Findings from our two-sample MR analysis identified dietary principal components described best as whole brain bread, wheat, cheese, oat cereal and red wine to be associated with higher educational attainment and other cognition-related phenotypes. CONCLUSION: Using genetics, we highlighted the potential role of HFSS food consumption and consumption of the components of a staple food diet for school performance. However, further research is required to find conclusive evidence that could support a causal role of diet on school performance.

Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7-89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Low and high serum IgG associates with respiratory infections in a young and working age population.

BACKGROUND: We investigated health consequences and genetic properties associated with serum IgG concentration in a young and working age general population. METHODS: Northern Finland Birth Cohort 1966 (NFBC1966, n = 12,231) health data have been collected from birth to 52 years of age. Relationships between life-long health events, medications, chronic conditions, lifestyle, and serum IgG concentration measured at age 46 years (n = 5430) were analysed. Regulatory mechanisms of serum IgG concentration were considered. FINDINGS: Smoking and genetic variation (FCGR2B and TNFRSF13B) were the most important determinants of serum IgG concentration. Laboratory findings suggestive of common variable immunodeficiency (CVID) were 10-fold higher compared to previous reports (73.7 per 100,000 vs 0.6-6.9 per 100,000). Low IgG was associated with antibiotic use (relative risk 1.285, 95% CI 1.001-1.648; p = 0.049) and sinus surgery (relative risk 2.257, 95% CI 1.163-4.379; p = 0.016). High serum IgG was associated with at least one pneumonia episode (relative risk 1.737, 95% CI 1.032-2.922; p = 0.038) and with total number of pneumonia episodes (relative risk 2.167, 95% CI 1.443-3.254; p < 0.001). INTERPRETATION: CVID-like laboratory findings are surprisingly common in our unselected study population. Any deviation of serum IgG from normal values can be harmful; both low and high serum IgG may indicate immunological insufficiency. Critical evaluation of clinical presentation must accompany immunological laboratory parameters. FUNDING: Oulu University Hospital VTR, CSL Behring, Foundation for Pediatric Research.

A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity.

Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74-2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.

Genetic fine-mapping from summary data using a nonlocal prior improves the detection of multiple causal variants.

MOTIVATION: Genome-wide association studies (GWAS) have been successful in identifying genomic loci associated with complex traits. Genetic fine-mapping aims to detect independent causal variants from the GWAS-identified loci, adjusting for linkage disequilibrium patterns. RESULTS: We present "FiniMOM" (fine-mapping using a product inverse-moment prior), a novel Bayesian fine-mapping method for summarized genetic associations. For causal effects, the method uses a nonlocal inverse-moment prior, which is a natural prior distribution to model non-null effects in finite samples. A beta-binomial prior is set for the number of causal variants, with a parameterization that can be used to control for potential misspecifications in the linkage disequilibrium reference. The results of simulations studies aimed to mimic a typical GWAS on circulating protein levels show improved credible set coverage and power of the proposed method over current state-of-the-art fine-mapping method SuSiE, especially in the case of multiple causal variants within a locus. AVAILABILITY AND IMPLEMENTATION: https://vkarhune.github.io/finimom/.

AMH as part of the diagnostic PCOS workup in large epidemiological studies.

OBJECTIVES: Previous studies have shown good correlation between polycystic ovarian morphology (PCOM) and serum anti-Müllerian hormone (AMH) levels. We evaluated the utility of AMH as a surrogate for PCOM as a part of the polycystic ovary syndrome (PCOS) diagnosis by describing how the use of different AMH cut-off values would change the prevalence of PCOS. METHODS: A general population-based birth cohort study. Anti-Müllerian hormone concentrations were measured from serum samples taken at age 31 years (n = 2917) using the electrochemiluminescence immunoassay (Elecsys). Anti-Müllerian hormone data were combined with data on oligo/amenorrhoea and hyperandrogenism to identify women with PCOS. RESULTS: The addition of AMH as a surrogate marker for PCOM increased the number of women fulfilling at least two PCOS features in accordance with the Rotterdam criteria. The prevalence of PCOS was 5.9% when using the AMH cut-off based on the 97.5% quartile (10.35 ng/mL) and 13.6% when using the recently proposed cut-off of 3.2 ng/mL. When using the latter cut-off value, the distribution of PCOS phenotypes A, B, C, and D was 23.9%, 4.7%, 36.6%, and 34.8%, respectively. Compared with the controls, all PCOS groups with different AMH concentration cut-offs showed significantly elevated testosterone (T), free androgen index (FAI), luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH) ratio, body mass index (BMI), waist circumference, and homoeostatic model assessment of insulin resistance (HOMA-IR) values, as well as significantly decreased sex hormone-binding globulin (SHBG) values. CONCLUSIONS: Anti-Müllerian hormone could be useful surrogate for PCOM in large data sets, where transvaginal ultrasound is not feasible, to aid the capturing of women with typical PCOS characteristics. Anti-Müllerian hormone measurement from archived samples enables retrospective PCOS diagnosis when combined with oligo/amenorrhoea or hyperandrogenism.