Genetic architecture of reciprocal social behavior in toddlers: Implications for heterogeneity in the early origins of autism spectrum disorder

Impairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism's heterogeneity.

Methodological Issues in Population-Based Studies of Multigenerational Associations

Laboratory-based animal research has revealed a number of exposures with multigenerational effects—ones that affect the children and grandchildren of those directly exposed. An important task for epidemiology is to investigate these relationships in human populations. Without the relative control achieved in laboratory settings, however, population-based studies of multigenerational associations have had to use a broader range of study designs. Current strategies to obtain multigenerational data include exploiting birth registries and existing cohort studies, ascertaining exposures within them, and measuring outcomes across multiple generations. In this paper, we describe the methodological challenges inherent to multigenerational studies in human populations. After outlining standard taxonomy to facilitate discussion of study designs and target exposure associations, we highlight the methodological issues, focusing on the interplay between study design, analysis strategy, and the fact that outcomes may be related to family size. In a simulation study, we show that different multigenerational designs lead to estimates of different exposure associations with distinct scientific interpretations. Nevertheless, target associations can be recovered by incorporating (possibly) auxiliary information, and we provide insights into choosing an appropriate target association. Finally, we identify areas requiring further methodological development.

Seasonality of birth defects in West Africa: could congenital Zika syndrome be to blame?

The link between Zika virus infection during pregnancy and microcephaly and other neurodevelopmental defects in infants, referred to as congenital Zika syndrome (CZS), was recently discovered. One key question that remains is whether such neurodevelopmental abnormalities are limited to the recently evolved Asiatic ZIKV strains or if they can also be induced by endemic African strains. Thus, we examined birth registries from one particular hospital from a country in West Africa, where ZIKV is endemic. Results showed a seasonal pattern of birth defects that is consistent with potential CZS, which corresponds to a range of presumed maternal infection that encompasses both the peak of the warm, rainy season as well as the months immediately following it, when mosquito activity is likely high. While we refrain from definitively linking ZIKV infection and birth defects in West Africa at this time, in part due to scant data available from the region, we hope that this report will initiate broader surveillance efforts that may help shed light onto mechanisms underlying CZS.

Healthy minds 0–100 years: Optimising the use of European brain imaging cohorts (“Lifebrain”)

The main objective of “Lifebrain” is to identify the determinants of brain, cognitive and mental (BCM) health at different stages of life. By integrating, harmonising and enriching major European neuroimaging studies across the life span, we will merge fine-grained BCM health measures of more than 5000 individuals. Longitudinal brain imaging, genetic and health data are available for a major part, as well as cognitive and mental health measures for the broader cohorts, exceeding 27,000 examinations in total. By linking these data to other databases and biobanks, including birth registries, national and regional archives, and by enriching them with a new online data collection and novel measures, we will address the risk factors and protective factors of BCM health. We will identify pathways through which risk and protective factors work and their moderators. Exploiting existing European infrastructures and initiatives, we hope to make major conceptual, methodological and analytical contributions towards large integrative cohorts and their efficient exploitation. We will thus provide novel information on BCM health maintenance, as well as the onset and course of BCM disorders. This will lay a foundation for earlier diagnosis of brain disorders, aberrant development and decline of BCM health, and translate into future preventive and therapeutic strategies. Aiming to improve clinical practice and public health we will work with stakeholders and health authorities, and thus provide the evidence base for prevention and intervention.

Seasonality of birth defects in West Africa: could congenital Zika syndrome be to blame?

The link between Zika virus infection during pregnancy and microcephaly and other neurodevelopmental defects in infants, referred to as congenital Zika syndrome (CZS), was recently discovered. One key question that remains is whether such neurodevelopmental abnormalities are limited to the recently evolved Asiatic ZIKV strains or if they can also be induced by endemic African strains. Thus, we examined birth registries from one particular hospital from a country in West Africa, where ZIKV is endemic. Results showed a seasonal pattern of birth defects that is consistent with potential CZS, which correspond to a range of presumed maternal infection that encompasses both the peak of the warm, rainy season as well as the months immediately following it, when mosquito activity is likely high. While we refrain from definitively linking ZIKV infection and birth defects in West Africa at this time, in part due to scant data available from the region, we hope that this report will initiate broader surveillance efforts that may help shed light onto mechanisms underlying CZS.

Perinatal characteristics and breast cancer risk in daughters: a Scandinavian population-based study

The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2–13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1–14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

The Right to a Father's Name: A Historical Perspective on State Efforts to Combat the Stigma of Illegitimate Birth in Brazil

Over the past decade, state agencies throughout Brazil have launched initiatives that aim to defend children's rights to their father's name. These initiatives take the form of discrete programs in different states, all of which seek to identify children who lack a paternal last name—an estimated 10–25 percent of all Brazilian children —in hopes of finding their fathers and encouraging or obligating them to legally recognize their paternity and inscribe their names on the children's birth registries. Project staff also sometimes formalize child support arrangements, although this is not the primary objective. Instead, Responsible Paternity projects (as most of them are known) seek to free children from the social stigma of illegitimate birth, thus protecting their constitutional right to equality and human dignity.