This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1,400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive and psychosocial factors.

IMPORTANCEMaternal tobacco use during pregnancy has been associated with various health consequences, including suboptimal neurodevelopment in offspring. However, the effect of prenatal exposure to maternal smoking on child brain development has yet to be elucidated. OBJECTIVE To investigate the association between maternal smoking during pregnancy and offspring brain development in preadolescence as well as the mediating pathways. DESIGN, SETTING, AND PARTICIPANTS This prospective, population-based cohort study was embedded in the Generation R Study, Rotterdam, the Netherlands. The Generation R Study was launched in 2002, with follow-up ongoing. Child brain morphology was assessed at 9 to 11 years of age (ie, 10-12 years between exposure and outcome assessment). Data analysis was performed from March 1, 2021, to February 28, 2022, and at the time of manuscript revision. Participants included the singleton children of pregnant women residing in the study area with an expected date of delivery between April 1, 2002, and January 31, 2006; 2704 children with information on maternal smoking during pregnancy and structural neuroimaging at 9 to 11 years of age were included. A subsample of 784 children with data on DNA methylation at birth was examined in the mediation analysis. EXPOSURES Information on maternal smoking during pregnancy was collected via a questionnaire in each trimester. As a contrast, paternal smoking was assessed at recruitment. MAIN OUTCOMES AND MEASURES Brain morphology, including brain volumes and surface-based cortical measures (thickness, surface area, and gyrification), was assessed with magnetic resonance imaging. For mediation analysis, DNA methylation at birth was quantified by a weighted methylation risk score. RESULTS The 2704 participating children (1370 [50.7%] girls and 1334 [49.3%] boys) underwent brain imaging assessment at a mean (SD) age of 10.1 (0.6) years. Compared with nonexposed children (n = 2102), exposure to continued maternal smoking during pregnancy (n = 364) was associated with smaller total brain volume (volumetric difference [b] = −14.5 [95% CI, −25.1 to −4.0] cm 3 ), cerebral gray matter volume (b = −7.8 [95% CI, −13.4 to −2.3] cm 3 ), cerebral white matter volume (b = −5.9 [95% CI, −10.7 to −1.0] cm 3 ), and surface area and less gyrification. These associations were not explained by paternal smoking nor mediated by smoking-associated DNA methylation patterns at birth. Children exposed to maternal smoking only in the first trimester (n = 238) showed no differences in brain morphology compared with nonexposed children. CONCLUSIONS AND RELEVANCEThe findings of this cohort study suggest that continued maternal tobacco use during pregnancy was associated with lower brain volumes and suboptimal cortical traits of offspring in preadolescence, which seemed to be independent of shared family (continued) Key Points Question Is maternal tobacco use during pregnancy associated with preadolescent brain morphology among offspring? Findings In this cohort study of 2704 children in ...

Psychopathology represents a leading cause of disability worldwide. Effective interventions need to target risk factors that are causally related to psychopathology. In order to distinguish between causal and spurious risk factors, it is critical to account for environmental and genetic confounding. Mendelian randomisation studies use genetic variants that are independent from environmental and genetic confounders in order to strengthen causal inference. We conducted a systematic review of studies (N = 19) using Mendelian randomisation to examine the causal role of putative risk factors for psychopathology-related outcomes including depression, anxiety, psychological distress, schizophrenia, substance abuse/antisocial behaviour, and smoking initiation. The most commonly examined risk factors in the reviewed Mendelian randomisation studies were smoking, alcohol use and body mass index. In most cases, risk factors were strongly associated with psychopathology-related outcomes in conventional analyses but Mendelian randomisation indicated that these associations were unlikely to be causal. However, Mendelian randomisation analyses showed that both smoking and homocysteine plasma levels may be causally linked with schizophrenia. We discuss possible reasons for these diverging results between conventional and Mendelian randomisation analyses and outline future directions for progressing research in ways that maximise the potential for identifying targets for intervention.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.