Application of the Instrumental Inequalities to a Mendelian Randomization Study With Multiple Proposed Instruments

BACKGROUND: Investigators often support the validity of Mendelian randomization (MR) studies, an instrumental variable approach proposing genetic variants as instruments, via. subject matter knowledge. However, the instrumental variable model implies certain inequalities, offering an empirical method of falsifying (but not verifying) the underlying assumptions. Although these inequalities are said to detect only extreme assumptio

Prenatal and perinatal risk factors for eating disorders in women: A population cohort study

Objective: The fetal programming model hypothesizes that developmental programming in utero and in early life induces adaptations that predetermine the adult phenotype. This study investigated whether prenatal/perinatal complications are associated with lifetime eating disorders in women. Method: Participants included 46,373 adult women enrolled in the Norwegian Mother and Child Cohort Study (den norske Mor & barn-undersøkelsen [MoBa]). MoBa mothers and their mothers (MoBa grandmothers) were the focus of the current study. MoBa mothers with lifetime eating disorders were compared to a referent group. Results: MoBa mothers who weighed more at birth (birth weight, adjusted odds ratio [OR] = 1.14; 95% confidence interval [CI]: 1.10–1.19) or were born large-for-gestational-age (adjusted OR = 1.39; 95% CI: 1.27–1.52) were more likely to develop binge-eating disorder in later life. MoBa mothers who weighed less at birth were more likely to develop anorexia nervosa (birth weight, adjusted OR = 0.88; 95% CI: 0.81–0.95). Bulimia nervosa and purging disorder (PD) were not significantly predicted by the prenatal and perinatal factors examined. Discussion: Results of this study, which include the first known investigation of prenatal and perinatal factors in binge-eating disorder and PD, suggest that fetal programming may be relevant to the development of anorexia nervosa and binge-eating disorder. Future genetically informative research is needed to help disentangle whether these associations are a function of genetic influences or a true environmental fetal programming effect

Mendelian randomisation approaches to the study of prenatal exposures: A systematic review

Background: Mendelian randomisation (MR) designs apply instrumental variable techniques using genetic variants to study causal effects. MR is increasingly used to evaluate the role of maternal exposures during pregnancy on offspring health. Objectives: We review the application of MR to prenatal exposures and describe reporting of methodologic challenges in this area. Data sources: We searched PubMed, EMBASE, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar. Study selection and data extraction: Eligible studies met the following criteria: (a) a maternal pregnancy exposure; (b) an outcome assessed in offspring of the pregnancy; and (c) a genetic variant or score proposed as an instrument or proxy for an exposure. Synthesis: We quantified the frequency of reporting of MR conditions stated, techniques used to examine assumption plausibility, and reported limitatio

Genome-wide association meta-analysis of childhood and adolescent internalising symptoms.

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (rg> 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (rangerg = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success