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Background Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10−3), and combined dataset (p = 1.1 × 10−4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10−35, loss-of-function p = 2.26 × 10−13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10−6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

To better understand the problems associated with diagnosis of bipolar disorder, especially problems related to race and ethnicity, this study compared whites, African Americans, and Latinos with bipolar I disorder in the presentation of manic symptoms, depressive episodes, functional impairments (Short Form-12), and self-reports of schizophrenia diagnosis. Data for this study were derived from the 2001 National Epidemiologic Survey on Alcohol and Related Conditions, which are nationally representative of United States households. African Americans and Latinos expressed similar rates in presentation of 14 out of 16 manic symptoms compared with whites, with the exception of grandiosity/self-esteem, in which they were more likely to exhibit this symptom compared with whites. Higher rates of depressive episodes were observed among whites, and these episodes occurred significantly earlier compared with African Americans and Latinos. Latinos had slightly higher vitality scores on the SF-12 measures after adjusting for sociodemographic and clinical factors, but no other differences across the groups were observed. Overall, these data show that the expression and functional impairments of bipolar I disorder is very similar across racial ethnic groups using this community-based sample. This is the first community-based study making such comparisons, with results suggesting that provider biases are more likely to explain problems in misdiagnosis than fundamental differences in the presentation of bipolar disorder across racial/ethnic groups.

Research findings remain unclear on whether different factors predict aggression for adolescent men and women. Given that aggression research is rarely conducted with Latin American populations, the current study used multiple imputation and linear regression to assess gender differences in levels and predictors of self-reported physical aggression among a community sample of young (ages 11 through 17) men (n=504) and women (n = 471) from Santiago, Chile. Results revealed that adolescent women reported engaging in higher levels of physical aggression than men. The variables found to be significantly associated with higher levels of reported aggression—younger age, less family involvement, less parental control, less positive relationships with caregivers, having more friends who act out and use substances, having fewer friends committed to learning, presence of dating violence, and more exposure to neighborhood crime—were not moderated by gender, implying that similar factors are related to aggression in adolescent men and women from Chile. Implications for prevention and intervention efforts to address high-risk adolescents and reduce aggression among Chilean youth are discussed.