Investigating the relationship between DNA methylation, genetic variation, and suicide attempt in bipolar disorder.

Individuals with bipolar disorder are at increased risk for suicide, and this can be influenced by a range of biological, clinical, and environmental risk factors. Biological components associated with suicide include DNA modifications that lead to changes in gene expression. Common genetic variation and DNA methylation changes are some of the most frequent types of DNA findings associated with an increased risk for suicidal behavior. Importantly, the interplay between genetic predisposition and DNA methylation patterns is becoming more prevalent in genetic studies. We hypothesized that DNA methylation patterns in specific loci already genetically associated with suicide would be altered in individuals with bipolar disorder and a history of suicide attempt. To test this hypothesis, we searched the literature to identify common genetic variants (N=34) previously associated with suicidal thoughts and behaviors in individuals with bipolar disorder. We then created a customized sequencing panel that covered our chosen genomic loci. We profiled DNA methylation patterns from blood samples collected from bipolar disorder participants with suicidal behavior (N=55) and without suicidal behavior (N=51). We identified seven differentially methylated CpG sites and five differentially methylated regions between the two groups. Additionally, we found that DNA methylation changes in MIF and CACNA1C were associated with lethality or number of suicide attempts. Finally, we identified three meQTLs in SIRT1 , IMPA2 , and INPP1 . This study illustrates that DNA methylation is altered in individuals with bipolar disorder and a history of suicide attempts in regions known to harbor suicide-related variants.

Lingo: an automated, web-based deep phenotyping platform for language ability.

Background: Language and the ability to communicate effectively are key factors in mental health and well-being. Despite this critical importance, research on language is limited by the lack of a scalable phenotyping toolkit. Methods: Here, we describe and showcase Lingo - a flexible online battery of language and nonverbal reasoning skills based on seven widely used tasks (COWAT, picture narration, vocal rhythm entrainment, rapid automatized naming, following directions, sentence repetition, and nonverbal reasoning). The current version of Lingo takes approximately 30 minutes to complete, is entirely open source, and allows for a wide variety of performance metrics to be extracted. We asked > 1,300 individuals from multiple samples to complete Lingo, then investigated the validity and utility of the resulting data. Results: We conducted an exploratory factor analysis across 14 features derived from the seven assessments, identifying five factors. Four of the five factors showed acceptable test-retest reliability (Pearson's R > 0.7). Factor 2 showed the highest reliability (Pearson's R = 0.95) and loaded primarily on sentence repetition task performance. We validated Lingo with objective measures of language ability by comparing performance to gold-standard assessments: CELF-5 and the VABS-3. Factor 2 was significantly associated with the CELF-5 "core language ability" scale (Pearson's R = 0.77, p-value < 0.05) and the VABS-3 "communication" scale (Pearson's R = 0.74, p-value < 0.05). Factor 2 was positively associated with phenotypic and genetic measures of socieconomic status. Interestingly, we found the parents of children with language impairments had lower Factor 2 scores (p-value < 0.01). Finally, we found Lingo factor scores were significantly predictive of numerous psychiatric and neurodevelopmental conditions. Conclusions: Together, these analyses support Lingo as a powerful platform for scalable deep phenotyping of language and other cognitive abilities. Additionally, exploratory analyses provide supporting evidence for the heritability of language ability and the complex relationship between mental health and language.

Cerebellar morphological differences and associations with extrinsic factors in bipolar disorder type I.

BACKGROUND: The neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Literature suggests differences in cerebellar activity and metabolism in BD, however findings on structural differences remain contradictory. Potential reasons include combining BD subtypes, small sample sizes, and potential moderators such as genetics, adverse childhood experiences (ACEs), and pharmacotherapy. METHODS: We collected 3 T MRI scans from participants with (N = 131) and without (N = 81) BD type I, as well as blood and questionnaires. We assessed differences in cerebellar volumes and explored potentially influential factors. RESULTS: The cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Proportionate cerebellar white matter volumes appeared larger with more ACEs, but this may result from reduced ICV. Time from onset and symptom burden were not associated with cerebellar volumes. Finally, taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume. LIMITATIONS: This study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions. CONCLUSIONS: These findings suggest that external factors, such as sedatives and childhood experiences, may influence cerebellum structure in BD and may mask underlying differences. Accounting for such variables may be critical for consistent findings in future studies.

The combination of autism and exceptional cognitive ability is associated with suicidal ideation.

Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability autistic individuals for factors that were predictive of suicidal ideation. In the first sample (N = 1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ ≥ 120 (Odds Ratio = 5.9, p=0.0007). In a separate sample of SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (combined N = 16,049, Odds Ratio = 6.8, p<2.2e-16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p<2.2e-16) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (N = 1,983, Z=2.16,p=0.03), with PGS for educational attainment trending in the same direction (Z=1.4,p=0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (N = 736, Z=2.28,p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.

Clinical autism subscales have common genetic liabilities that are heritable, pleiotropic, and generalizable to the general population.

The complexity of autism's phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is undetermined if autistic symptom domain severity underlying this heterogeneity is heritable and pleiotropic with other psychiatric and behavior traits in the same manner as autism case-control status. In N = 6064 autistic children in the SPARK cohort, we investigated the common genetic properties of twelve subscales from three clinical autism instruments measuring autistic traits: the Social Communication Questionnaire (SCQ), the Repetitive Behavior Scale-Revised (RBS-R), and the Developmental Coordination Disorder Questionnaire (DCDQ). Educational attainment polygenic scores (PGS) were significantly negatively correlated with eleven subscales, while ADHD and major depression PGS were positively correlated with ten and eight of the autism subscales, respectively. Loneliness and neuroticism PGS were also positively correlated with many subscales. Significant PGS by sex interactions were found-surprisingly, the autism case-control PGS was negatively correlated in females and had no strong correlation in males. SNP-heritability of the DCDQ subscales ranged from 0.04 to 0.08, RBS-R subscales ranged from 0.09 to 0.24, and SCQ subscales ranged from 0 to 0.12. GWAS in SPARK followed by estimation of polygenic scores (PGS) in the typically-developing ABCD cohort (N = 5285), revealed significant associations of RBS-R subscale PGS with autism-related behavioral traits, with several subscale PGS more strongly correlated than the autism case-control PGS. Overall, our analyses suggest that the clinical autism subscale traits show variability in SNP-heritability, PGS associations, and significant PGS by sex interactions, underscoring the heterogeneity in autistic traits at a genetic level. Furthermore, of the three instruments investigated, the RBS-R shows the greatest evidence of genetic signal in both (1) autistic samples (greater heritability) and (2) general population samples (strongest PGS associations).