Maternal Smoking During Pregnancy and Offspring Birth Weight: A Genetically-Informed Approach Comparing Multiple Raters

Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the fetus. There is considerable debate about the best method of assessing SDP, including birth/medical records, timeline follow-back approaches, multiple reporters, and biological verification (e.g., cotinine). This is particularly salient for genetically-informed approaches where it is not always possible or practical to do a prospective study starting during the prenatal period when concurrent biological specimen samples can be collected with ease. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we: (1) compare rates of agreement across different types of report—maternal report of SDP, paternal report of maternal SDP, and SDP contained on birth records from the Department of Vital Statistics; (2) examine whether SDP is predictive of birth weight outcomes using our best SDP report as identified via step (1); and (3) use a sibling-comparison approach that controls for genetic and familial influences that siblings share in order to assess the effects of SDP on birth weight. Results show high agreement between reporters and support the utility of retrospective report of SDP. Further, we replicate a causal association between SDP and birth weight, wherein SDP results in reduced birth weight even when accounting for genetic and familial confounding factors via a sibling comparison approac

Missouri mothers and their children: A family study of the effects of genetics and the prenatal environment

The Missouri Mothers and Their Children Study was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record database. Interview and lab-based data were obtained from (1) mothers of Missouri-born children (born 1998–2005), who smoked during one pregnancy but not during another pregnancy, (2) biological fathers when available, and (3) the children [i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP)]. This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre-, peri- and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance use initiation

Passive \u3cem\u3er\u3c/em\u3eGE or Developmental Gene-Environment Cascade? An Investigation of the Role of Xenobiotic Metabolism Genes in the Association Between Smoke Exposure During Pregnancy and Child Birth Weight

There is considerable evidence that smoke exposure during pregnancy (SDP) environmentally influences birth weight after controlling for genetic influences and maternal characteristics. However, maternal smoking during pregnancy—the behavior that leads to smoke exposure during pregnancy—is also genetically-influenced, indicating the potential role of passive gene-environment correlation. An alternative to passive gene-SDP correlation is a cascading effect whereby maternal and child genetic influences are causally linked to prenatal exposures, which then have an ‘environmental’ effect on the development of the child’s biology and behavior. We describe and demonstrate a conceptual framework for disentangling passive rGE from this cascading GE effect using a systems-based polygenic scoring approach comprised of genes shown to be important in the xenobiotic (substances foreign to the body) metabolism pathway. Data were drawn from 5044 families from the Avon Longitudinal Study of Parents and Children with information on maternal SDP, birth weight, and genetic polymorphisms in the xenobiotic pathway. Within a k-fold cross-validation approach (k = 5), we created weighted maternal and child polygenic scores using 18 polymorphisms from 10 genes that have been implicated in the xenobiotic metabolism pathway. Mothers and children shared variation in xenobiotic metabolism genes. Amongst mothers who smoked during pregnancy, neither maternal nor child xenobiotic metabolism polygenic scores were associated with a higher likelihood of smoke exposure during pregnancy, or the severity of smoke exposure during pregnancy (and therefore, neither proposed mechanism was supported), or with child birth weight. SDP was consistently associated with lower child birth weight controlling for the polygenic scores, maternal educational attainment, social class, psychiatric problems, and age. Limitations of the study design and the potential of the framework using other designs are discussed

The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07

Environmental, dietary and case-control study of Nodding Syndrome in Uganda: A post-measles brain disorder triggered by malnutrition?

AbstractNodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among children (aged 5–18years) of Kitgum District, northern Uganda (Acholiland). Data on food availability, rainfall, and prevalent disease temporally related to the NS epidemic were also analyzed. In NS Cases, the mean age of reported head nodding onset was 7.6years (range 1–17years). The epidemiologic curve of NS incidence spanned 2000–2013, with peaks in 2003 and 2008. Month of onset of head nodding was non-uniform, with all-year-aggregated peaks in April and June when food availability was low. Families with one or more NS Cases had been significantly more dependent on emergency food and, immediately prior to head nodding onset in the child, subsistence on moldy plant materials, specifically moldy maize. Medical history revealed a single significant association with NS, namely prior measles infection. NS is compared with the post-measles disorder subacute sclerosing panencephalitis, with clinical expression triggered by factors associated with poor nutrition

Enriching Education with Exemplars in Practice: Iterative Development of Data Curation Internships

Partnerships between educational programs and research centers are vital to meeting the escalating workforce demands in data curation. They offer a platform for educators to increase their knowledge of current best practices and emerging challenges in the field. Student internships can be key to the success of these partnerships, not just for the students who gain authentic experience in facilities that excel at data intensive research and data services. Such partnerships provide an effective platform for rich and mutually beneficial engagement among educators, data professionals, scientists, and students. This paper reports on results from the Data Curation Education in Research Centers (DCERC) program aimed at developing a model for data curation education featuring field experiences in exemplar research centers. A strength of the DCERC model is its emphasis on facilitating mutual exchange of information among the DCERC program mentors and students. This model has evolved as a result of iterative and gradual refinements to the program model based upon information gathered from the formative evaluation. These refinements not only resulted in improved outcomes for the program participants but also, we believe, a more sustainable model for the program that leverages the knowledge base of the research scientists and students through peer-to-peer learning, rather than a traditional expert to trainee model. This paper describes formative evaluation findings that shaped the development of the DCERC program. We conclude with a discussion of the critical features of this model for the development of similar programs, and a data curation workforce that is able to accommodate and adapt to emergent data needs in a variety of environments

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry

Introduction: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. Methods: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, mu(age) = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerstrom Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. Results: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (beta = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. Conclusions: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.Peer reviewe

Multi-omic and multi-species meta-analyses of nicotine consumption.

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the \u27model organism geneset\u27 will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5-36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60-31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes