Proteome-Wide Assessment of Clustering of Missense Variants in Neurodevelopmental Disorders Versus Cancer.

Missense de novo variants (DNVs) and missense somatic variants contribute to neurodevelopmental disorders (NDDs) and cancer, respectively. Proteins with statistical enrichment based on analyses of these variants exhibit convergence in the differing NDD and cancer phenotypes. Herein, the question of why some of the same proteins are identified in both phenotypes is examined through investigation of clustering of missense variation at the protein level. Our hypothesis is that missense variation is present in different protein locations in the two phenotypes leading to the distinct phenotypic outcomes. We tested this hypothesis in 1D protein space using our software CLUMP. Furthermore, we newly developed 3D-CLUMP that uses 3D protein structures to spatially test clustering of missense variation for proteome-wide significance. We examined missense DNVs in 39,883 parent-child sequenced trios with NDDs and missense somatic variants from 10,543 sequenced tumors covering five TCGA cancer types and two COSMIC pan-cancer aggregates of tissue types. There were 57 proteins with proteome-wide significant missense variation clustering in NDDs when compared to cancers and 79 proteins with proteome-wide significant missense clustering in cancers compared to NDDs. While our main objective was to identify differences in patterns of missense variation, we also identified a novel NDD protein BLTP2. Overall, our study is innovative, provides new insights into differential missense variation in NDDs and cancer at the protein-level, and contributes necessary information toward building a framework for thinking about prognostic and therapeutic aspects of these proteins.

Investigating the Relationship Between Smoking Behavior and Global Brain Volume.

Background: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate directionality: Bradford Hill's criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis. Methods: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume. Results: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = -2964 mm3, p = 2.04 × 10-16), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10-84), but only modestly associated with total gray matter volume (effect size = -424 mm3, p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. Conclusions: A history of daily smoking is strongly associated with a decreased total brain volume.

The Promise of Polygenic Risk Prediction in Smoking Cessation: Evidence From Two Treatment Trials.

INTRODUCTION: Tobacco use disorder is a complex behavior with a strong genetic component. Genome-wide association studies (GWAS) on smoking behaviors allow for the creation of polygenic risk scores (PRSs) to approximate genetic vulnerability. However, the utility of smoking-related PRSs in predicting smoking cessation in clinical trials remains unknown. AIMS AND METHODS: We evaluated the association between polygenic risk scores and bioverified smoking abstinence in a meta-analysis of two randomized, placebo-controlled smoking cessation trials. PRSs of smoking behaviors were created using the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium summary statistics. We evaluated the utility of using individual PRS of specific smoking behavior versus a combined genetic risk that combines PRS of all four smoking behaviors. Study participants came from the Transdisciplinary Tobacco Use Research Centers (TTURCs) Study (1091 smokers of European descent), and the Genetically Informed Smoking Cessation Trial (GISC) Study (501 smokers of European descent). RESULTS: PRS of later age of smoking initiation (OR [95% CI]: 1.20, [1.04-1.37], p = .0097) was significantly associated with bioverified smoking abstinence at end of treatment. In addition, the combined PRS of smoking behaviors also significantly predicted bioverified smoking abstinence (OR [95% CI] 0.71 [0.51-0.99], p = .045). CONCLUSIONS: PRS of later age at smoking initiation may be useful in predicting smoking cessation at the end of treatment. A combined PRS may be a useful predictor for smoking abstinence by capturing the genetic propensity for multiple smoking behaviors. IMPLICATIONS: There is a potential for polygenic risk scores to inform future clinical medicine, and a great need for evidence on whether these scores predict clinically meaningful outcomes. Our meta-analysis provides early evidence for potential utility of using polygenic risk scores to predict smoking cessation amongst smokers undergoing quit attempts, informing further work to optimize the use of polygenic risk scores in clinical care.

Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample.

Background: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees. Objectives: We aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample. Methods: We used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI. Results: The PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts (q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes. Conclusions: Our results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors.

An update on the role of common genetic variation underlying substance use disorders.

PURPOSE OF THE REVIEW: Sample size increases have resulted in novel and replicable loci for substance use disorders (SUDs). We summarize some of the latest insights into SUD genetics and discuss some next steps in addiction genetics. RECENT FINDINGS: Genome-wide association studies have substantiated the role of previously known variants (e.g., rs1229984 in ADH1B for alcohol) and identified several novel loci for alcohol, tobacco, cannabis, opioid and cocaine use disorders. SUDs are genetically correlated with psychiatric outcomes, while liability to substance use is inconsistently associated with these outcomes and more closely associated with lifestyle factors. Specific variant associations appear to differ somewhat across populations, although similar genes and systems are implicated. SUMMARY: The next decade of human genetic studies of addiction should focus on expanding to non-European populations, consider pleiotropy across SUD and with other psychiatric disorders, and leverage human and cross-species functional data to elucidate the biological mechanisms underlying SUDs.