Nicola Barban

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 influence on age at first birth of female twins born in the UK, 1919-68

Using a sample of monozygotic (945, 42 per cent) and dizygotic (1,329, 58 per cent) twin pairs born 1919–68 in the UK, we applied innovative tobit models to investigate genetic and environmental influences on age at first birth (AFB). We found that a substantial part (40 per cent) of the variation in AFB is caused by latent family characteristics. Genetic dispositions (26 per cent) play a more important role than the shared environment of siblings (14 per cent), with the non-shared environment/measurement error having the strongest influence (60 per cent). Like previous studies, this study reveals marked changes in estimates over time, and supports the idea that environmental constraints (war or economic crisis) suppress and normative freedom (sexual revolution) promotes the activation of genetic predispositions that affect fertility. We show that the exclusion of censored information (i.e., on the childless) by previous studies biased their results. Supplementary material for this article is available at: http://dx.doi.org/10.1080/00324728.2015.1056823

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

IMPORTANCE A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the fathers age. RESULTS We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Causal Effects of the Timing of Life-course Events Age at Retirement and Subsequent Health

In this article, we combine the extensive literature on the analysis of life-course trajectories as sequences with the literature on causal inference and propose a new matching approach to investigate the causal effect of the timing of life-course events on subsequent outcomes. Our matching approach takes into account pre-event confounders that are both time-independent and time-dependent as well as life-course trajectories. After matching, treated and control individuals can be compared using standard statistical tests or regression models. We apply our approach to the study of the consequences of the age at retirement on subsequent health outcomes, using a unique data set from Swedish administrative registers. Once selectivity in the timing of retirement is taken into account, effects on hospitalization are small, while early retirement has negative effects on survival. Our approach also allows for heterogeneous treatment effects. We show that the effects of early retirement differ according to preretirement income, with higher income individuals tending to benefit from early retirement, while the opposite is true for individuals with lower income.