Development of Social Variation in Reproductive Schedules: A Study from an English Urban Area

Background: There is striking social variation in the timing of the onset of childbearing in contemporary England, with the mean age at first motherhood about 8 years earlier in the most deprived compared to the least deprived neighbourhoods. However, relatively little is known about how these social differences in reproductive schedule develop in childhood. Methodology/Principal Findings: We studied the development of differences in reproductive schedules, using a crosssectional survey over 1000 school students aged 9–15 in the metropolitan borough of North Tyneside. Students from more deprived neighbourhoods had earlier ideal ages for parenthood than those from more affluent ones, and these differences were fully apparent by age 11. We found evidence consistent with three mechanisms playing a role in maintaining the socioeconomic gradient. These were: vertical intergenerational transmission (students whose own parents were younger at their birth wanted children younger); oblique intergenerational transmission (students in neighbourhoods where parents were younger in general wanted children earlier); and low parental investment (students who did not feel emotionally supported by their own parents wanted children at a younger age). Conclusions/Significance: Our results shed some light on the proximate factors which may be involved in maintaining early childbearing in disadvantaged communities. They help understand why educational initiatives aimed at adolescents tend to have no effect, whereas improving the well-being of poor families with young children may do so. Our results also sugges

Multivariate genomic scan implicates novel loci and haem metabolism in human ageing

Ageing phenotypes are of great interest but are difficult to study genetically, partly due to the sample sizes required. Here, the authors present a multivariate framework to combine GWAS summary statistics and increase statistical power, identifying additional loci enriched for aging

An interaction map of circulating metabolites, immune gene networks, and their genetic regulation

Background: Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up.Results: We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus.Conclusions: This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure

Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants.Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression.Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure

Human Fertility, Molecular Genetics, and Natural Selection in Modern Societies

Research on genetic influences on human fertility outcomes such as number of children ever born (NEB) or the age at first childbirth (AFB) has been solely based on twin and family-designs that suffer from problematic assumptions and practical limitations. The current study exploits recent advances in the field of molecular genetics by applying the genomic-relationship-matrix based restricted maximum likelihood (GREML) methods to quantify for the first time the extent to which common genetic variants influence the NEB and the AFB of women. Using data from the UK and the Netherlands (N = 6,758), results show significant additive genetic effects on both traits explaining 10% (SE = 5) of the variance in the NEB and 15% (SE = 4) in the AFB. We further find a significant negative genetic correlation between AFB and NEB in the pooled sample of –0.62 (SE = 0.27, p-value = 0.02). This finding implies that individuals with genetic predispositions for an earlier AFB had a reproductive advantage and that natural selection operated not only in historical, but also in contemporary populations. The observed postponement in the AFB across the past century in Europe contrasts with these findings, suggesting an evolutionary override by environmental effects and underscoring that evolutionary predictions in modern human societies are not straight forward. It emphasizes the necessity for an integrative research design from the fields of genetics and social sciences in order to understand and predict fertility outcomes. Finally, our results suggest that we may be able to find genetic variants associated with human fertility when conducting GWAS-meta analyses with sufficient sample size

Genetic links between post-reproductive lifespan and family size in Framingham.

BACKGROUND AND OBJECTIVES: Is there a trade-off between children ever born (CEB) and post-reproductive lifespan in humans? Here, we report a comprehensive analysis of reproductive trade-offs in the Framingham Heart Study (FHS) dataset using phenotypic and genotypic correlations and a genome-wide association study (GWAS) to look for single-nucleotide polymorphisms (SNPs) that are related to the association between CEB and lifespan. METHODOLOGY: We calculated the phenotypic and genetic correlations of lifespan with CEB for men and women in the Framingham dataset, and then performed a GWAS to search for SNPs that might affect the relationship between post-reproductive lifespan and CEB. RESULTS: We found significant negative phenotypic correlations between CEB and lifespan in both women (rP = -0.133, P < 0.001) and men (rP = -0. 079, P = 0.036). The genetic correlation was large, highly significant and strongly negative in women (rG = -0.877, P = 0.009) in a model without covariates, but not in men (P = 0.777). The GWAS identified five SNPs associated with the relationship between CEB and post-reproductive lifespan in women; some are near genes that have been linked to cancer. None were identified in men. CONCLUSIONS AND IMPLICATIONS: We identified several SNPs for which the relationship between CEB and post-reproductive lifespan differs by genotype in women in the FHS who were born between 1889 and 1958. That result was not robust to changes in the sample. Further studies on larger samples are needed to validate the antagonistic pleiotropy of these genes

Opposite differential risks for autism and schizophrenia based on maternal age, paternal age, and parental age differences

BACKGROUND AND OBJECTIVES: Effects of maternal and paternal age on offspring autism and schizophrenia risks have been studied for over three decades, but inconsistent risks have often been found, precluding well-informed speculation on why these age-related risks might exist. METHODOLOGY: To help clarify this situation we analysed a massive single population sample from Denmark including the full spectrum of autistic and schizophrenic disorders (eliminating between-study confounding), used up to 30 follow-up years, controlled for over 20 potentially confounding factors and interpret the ultimate causation of the observed risk patterns using generally accepted principles of parent-offspring conflict and life-history theory. RESULTS: We evaluated the effects of paternal age, maternal age and parental age difference on offspring mental disorders and found consistently similar risk patterns for related disorders and markedly different patterns between autistic and schizophrenic disorders. Older fathers and mothers both conferred increased risk for autistic but not schizophrenic disorders, but autism risk was reduced in younger parents and offspring of younger mothers had increased risk for many schizophrenic disorders. Risk for most disorders also increased when parents were more dissimilarly aged. Monotonically increasing autism risk is consistent with mutation accumulation as fathers' age, but this explanation is invalid for schizophrenic disorders, which were not related to paternal age and were negatively correlated with maternal age. CONCLUSIONS AND IMPLICATIONS: We propose that the observed maternally induced risk patterns ultimately reflect a shifting ancestral life-history trade-off between current and future reproduction, mediated by an initially high but subsequently decreasing tendency to constrain foetal provisioning as women proceed from first to final pregnancy