A genetic exploration of the relationship between Posttraumatic Stress Disorder and cardiovascular diseases.

Background and Aims: Experiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascular disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD. Methods: We leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibrillation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomization to examine causal pathways between PTSD and CVD, incorporating the same potential mediators. Results: Significant genetic correlations were found between PTSD and CAD, HT, and HF (rg =0.21-0.32, p≤ 3.08 · 10-16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained. Conclusions: In addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients.

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.

PURPOSE: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. METHODS: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. RESULTS: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). CONCLUSIONS: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10-18), CanUD (rg = 0.37, p = 8.21 × 10-37), OUD (rg = 0.20, p = 1.50 × 10-3), and PTU (rg = 0.29, p = 8.53 × 10-12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10-4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10-6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10-8; pain-outcome: beta = 0.09, p = 3.05 × 10-6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10-8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10-5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Unraveling COVID-19 relationship with anxiety disorders and symptoms using genome-wide data.

BACKGROUND: There is still a limited understanding of the dynamics contributing to the comorbidity of COVID-19 and anxiety outcomes. METHODS: To dissect the pleiotropic mechanisms contributing to COVID-19/anxiety comorbidity, we used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls). Specifically, we assessed global and local genetic correlation and genetically inferred effects linking COVID-19 outcomes (infection, hospitalization, and severe respiratory symptoms) to anxiety disorders and symptoms. RESULTS: We observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg = 0.35, p = 2×10-4) and COVID-19 hospitalization (rg = 0.31, p = 7.2×10-4). Among anxiety symptoms, "Tense, sore, or aching muscles during worst period of anxiety" was genetically correlated with COVID-19 positive status (rg = 0.33, p = 0.001), while "Frequent trouble falling or staying asleep during worst period of anxiety" was genetically correlated with COVID-19 hospitalization (rg = 0.24, p = 0.004). Through a latent causal variable analysis, we observed that COVID-19 outcomes have statistically significant genetic causality proportion (gcp) on anxiety symptoms (e.g., COVID-19 positive status→"Recent easy annoyance or irritability" │gcp│ = 0.18, p = 6.72×10-17). Conversely, anxiety disorders appear to have a possible causal effect on COVID-19 (│gcp│ = 0.38, p = 3.17×10-9). Additionally, we also identified multiple loci with evidence of local genetic correlation between anxiety and COVID-19. These appear to be related to genetic effects shared with lung function, brain morphology, alcohol and tobacco use, and hematologic parameters. CONCLUSIONS: This study provided insights into the pleiotropic mechanisms linking COVID-19 and anxiety outcomes, suggesting differences between dynamics related to anxiety disorders and those related to anxiety symptoms.

Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association With Cardiometabolic and Respiratory Outcomes.

Importance: Posttraumatic stress disorder (PTSD) has been reported to be a risk factor for several physical and somatic symptoms. However, the genetics of PTSD and its potential association with medical outcomes remain unclear. Objective: To examine disease categories and laboratory tests from electronic health records (EHRs) that are associated with PTSD polygenic scores. Design, Setting, and Participants: This genetic association study was conducted from July 15, 2021, to January 24, 2023, using EHR data from participants across 4 biobanks. The polygenic scores of PTSD symptom severity (PGS-PTSD) were tested with all available phecodes in Vanderbilt University Medical Center's biobank (BioVU), Mass General Brigham (MGB), Michigan Genomics Initiative (MGI), and UK Biobank (UKBB). The significant medical outcomes were tested for overrepresented disease categories and subsequently tested for genetic correlation and 2-sample mendelian randomization (MR) to determine genetically informed associations. Multivariable MR was conducted to assess whether PTSD associations with health outcomes were independent of the genetic effect of body mass index and tobacco smoking. Exposures: Polygenic score of PTSD symptom severity. Main Outcomes and Measures: A total of 1680 phecodes (ie, International Classification of Diseases, Ninth Revision- and Tenth Revision-based phenotypic definitions of health outcomes) across 4 biobanks and 490 laboratory tests across 2 biobanks (BioVU and MGB). Results: In this study including a total of 496 317 individuals (mean [SD] age, 56.8 [8.0] years; 263 048 female [53%]) across the 4 EHR sites, meta-analyzing associations of PGS-PTSD with 1680 phecodes from 496 317 individuals showed significant associations to be overrepresented from mental health disorders (fold enrichment = 3.15; P = 5.81 × 10-6), circulatory system (fold enrichment = 3.32; P = 6.39 × 10-12), digestive (fold enrichment = 2.42; P = 2.16 × 10-7), and respiratory outcomes (fold enrichment = 2.51; P = 8.28 × 10-5). The laboratory measures scan with PGS-PTSD in BioVU and MGB biobanks revealed top associations in metabolic and immune domains. MR identified genetic liability to PTSD symptom severity as an associated risk factor for 12 health outcomes, including alcoholism (ß = 0.023; P = 1.49 × 10-4), tachycardia (ß = 0.045; P = 8.30 × 10-5), cardiac dysrhythmias (ß = 0.016, P = 3.09 × 10-5), and acute pancreatitis (ß = 0.049, P = 4.48 × 10-4). Several of these associations were robust to genetic effects of body mass index and smoking. We observed a bidirectional association between PTSD symptoms and nonspecific chest pain and C-reactive protein. Conclusions and Relevance: Results of this study suggest the broad health repercussions associated with the genetic liability to PTSD across 4 biobanks. The circulatory and respiratory systems association was observed to be overrepresented in all 4 biobanks.

Characterizing the polygenic architecture of complex traits in populations of East Asian and European descent.

To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (π c ). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for π c differences related to hematological and metabolic traits (hematological fold-enrichment=4.45, p=2.15×10 -7 ; metabolic fold-enrichment=4.05, p=4.01×10 -6 ). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median π c =0.15%, EAS-metabolic median π c =0.18%) with the strongest π c difference with respect to respiratory traits (EAS-respiratory median π c =0.50%; Hematological-p=2.26×10 -3 ; Metabolic-p=3.48×10 -3 ). In EUR, pairwise comparisons showed multiple π c differences related to the endocrine category (fold-enrichment=5.83, p=4.76×10 -6 ), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median π c =0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median π c =0.50%; p=1.19×10 -4 ). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p=2.18×10 -4 ; EUR endocrine-gastrointestinal p=6.80×10 -4 ). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.

Characterizing the polygenic architecture of complex traits in populations of East Asian and European descent.

To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (πc). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for πc differences related to hematological and metabolic traits (hematological fold-enrichment = 4.45, p = 2.15 × 10-7; metabolic fold-enrichment = 4.05, p = 4.01 × 10-6). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median πc = 0.15%, EAS-metabolic median πc = 0.18%) with the strongest πc difference with respect to respiratory traits (EAS-respiratory median πc = 0.50%; hematological-p = 2.26 × 10-3; metabolic-p = 3.48 × 10-3). In EUR, pairwise comparisons showed multiple πc differences related to the endocrine category (fold-enrichment = 5.83, p = 4.76 × 10-6), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median πc = 0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median πc = 0.50%; p = 1.19 × 10-4). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p = 2.18 × 10-4; EUR endocrine-gastrointestinal p = 6.80 × 10-4). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.

Unraveling COVID-19 Relationship with Anxiety Disorders and Symptoms.

Background: While COVID-19 outcomes are associated with increased anxiety, individuals affected by anxiety disorders are more likely to develop severe COVID-19 outcomes. Methods: We used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls) to investigate possible causal effects and shared genetic mechanisms linking COVID-19 outcomes to anxiety disorders and symptoms. Results: We observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg=0.35, p=2 × 10 -4 ) and COVID-19 hospitalization (rg=0.31, p=7.2 × 10 -4 ). Among anxiety symptoms, "Tense, sore, or aching muscles during worst period of anxiety" was genetically correlated with COVID-19 positive status (rg=0.33, p=0.001), while "Frequent trouble falling or staying asleep during worst period of anxiety" was genetically correlated with COVID-19 hospitalization (rg=0.24, p=0.004). Through a latent causal variable analysis, we observed that COVID-19 outcomes have statistically significant genetic causality proportion (gcp) on anxiety symptoms (e.g., COVID-19 positive status→"Recent easy annoyance or irritability" │gcp│=0.18, p=6.72 × 10 -17 ). Conversely, anxiety disorders appear to have a possible causal effect on COVID-19 (│gcp│=0.38, p=3.17 × 10 -9 ). Additionally, we also identified multiple loci with evidence of local genetic correlation between anxiety and COVID-19. These appear to be related to genetic effects shared with lung function, brain morphology, alcohol and tobacco use, and hematologic parameters. Conclusions: This study provided important insights into the relationship between COVID-19 and mental health, differentiating the dynamics linking anxiety disorders to COVID-19 from the effect of COVID-19 on anxiety symptoms.

Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.

Sex differences in the polygenic architecture of hearing problems in adults.

BACKGROUND: Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies. METHODS: Leveraging the UK Biobank, the Nurses' Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors. RESULTS: We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes. CONCLUSIONS: The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

An Atlas of Genetic Correlations and Genetically Informed Associations Linking Psychiatric and Immune-Related Phenotypes.

Importance: Certain psychiatric and immune-related disorders are reciprocal risk factors. However, the nature of these associations is unclear. Objective: To characterize the pleiotropy between psychiatric and immune-related traits, as well as risk factors of hypothesized relevance. Design, Setting, and Participants: This genetic association study was conducted from July 10, 2020, to January 15, 2022. Analyses used genome-wide association (GWA) statistics related to 14 psychiatric traits; 13 immune-related phenotypes, ie, allergic, autoimmune, and inflammatory disorders; and 15 risk factors related to health-related behaviors, social determinants of health, and stress response. Genetically correlated psychiatric-immune pairs were assessed using 2-sample mendelian randomization (MR) with sensitivity analyses and multivariable adjustment for genetic associations of third variables. False discovery rate correction (Q value < .05) was applied for each analysis. Exposures: Genetic associations. Main Outcomes and Measures: Genetic correlations and MR association estimates with SEs and P values. A data-driven approach was used that did not test a priori planned hypotheses. Results: A total of 44 genetically correlated psychiatric-immune pairs were identified, including 31 positive correlations (most consistently involving asthma, Crohn disease, hypothyroidism, and ulcerative colitis) and 13 negative correlations (most consistently involving allergic rhinitis and type 1 diabetes). Correlations with third variables were especially strong for psychiatric phenotypes. MR identified 7 associations of psychiatric phenotypes on immune-related phenotypes that were robust to multivariable adjustment, including the positive association of (1) the psychiatric cross-disorder phenotype with asthma (odds ratio [OR], 1.04; 95% CI, 1.02-1.06), Crohn disease (OR, 1.09; 95% CI, 1.05-1.14), and ulcerative colitis (OR, 1.09; 95% CI, 1.05-1.14); (2) major depression with asthma (OR, 1.25; 95% CI, 1.13-1.37); (3) schizophrenia with Crohn disease (OR, 1.12; 95% CI, 1.05-1.18) and ulcerative colitis (OR, 1.14; 95% CI, 1.07-1.21); and a negative association of risk tolerance with allergic rhinitis (OR, 0.77; 95% CI, 0.67-0.92). Conclusions and Relevance: Results of this genetic association study suggest that genetic liability for psychiatric disorders was associated with liability for several immune disorders, suggesting that vertical pleiotropy related to behavioral traits (or correlated third variables) contributes to clinical associations observed in population-scale data.

The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic transthyretin expression.

Transthyretin (TTR) is the precursor of the fibrils that compromise organ function in hereditary and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. In the present study, we leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the Genotype-Tissue Expression project to test the association of genetically regulated TTR gene expression with 7149 traits assessed in 420,531 individuals. We conducted a multi-tissue analysis of TTR transcription and identified an association with a operational procedure related to bone fracture (p = 5.46×10-6). Using tissue-specific TTR expression information, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, p = 9.51×10-5). Using the UK Biobank electronic health records (EHRs), we investigated the comorbidities affecting individuals undergoing this surgical procedure. Excluding bone fracture EHRs, we identified a pattern of health outcomes previously associated with ATTR manifestations. These included osteoarthritis (OR = 3.18, p = 9.18×10-8), carpal tunnel syndrome (OR = 2.15, p = .002), and a history of gastrointestinal diseases (OR = 2.01, p = 8.07×10-4). In conclusion, our study supports that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein.

Drinking and smoking polygenic risk is associated with childhood and early-adulthood psychiatric and behavioral traits independently of substance use and psychiatric genetic risk.

Alcohol drinking and tobacco smoking are hazardous behaviors associated with a wide range of adverse health outcomes. In this study, we explored the association of polygenic risk scores (PRS) related to drinks per week, age of smoking initiation, smoking initiation, cigarettes per day, and smoking cessation with 433 psychiatric and behavioral traits in 4498 children and young adults (aged 8-21) of European ancestry from the Philadelphia neurodevelopmental cohort. After applying a false discovery rate multiple testing correction accounting for the number of PRS and traits tested, we identified 36 associations related to psychotic symptoms, emotion and age recognition social competencies, verbal reasoning, anxiety-related traits, parents' education, and substance use. These associations were independent of the genetic correlations among the alcohol-drinking and tobacco-smoking traits and those with cognitive performance, educational attainment, risk-taking behaviors, and psychopathology. The removal of participants endorsing substance use did not affect the associations of each PRS with psychiatric and behavioral traits identified as significant in the discovery analyses. Gene-ontology enrichment analyses identified several neurobiological processes underlying mechanisms of the PRS associations we report. In conclusion, we provide novel insights into the genetic overlap of smoking and drinking behaviors in children and young adults, highlighting their independence from psychopathology and substance use.

Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality.

Substance dependence diagnoses (SDs) are important risk factors for suicidality. We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (N = 15,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (N = 11,236) was recruited to evaluate mental health risk and resilience among Army personnel. We applied multivariate logistic regression to investigate the associations of SDs with suicidality and, in the Yale-Penn cohort, we used the structured linear mixed model (StructLMM) to study multivariate gene-environment interactions. In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidality: having five SDs showed an association with suicidality, from odds ratio (OR) = 6.77 (95% confidence interval, CI = 5.74-7.99) for suicidal ideation (SI) to OR = 3.61 (95% CI = 2.7-4.86) for suicide attempt (SA). In Army STARRS, having multiple substance use disorders for alcohol and/or drugs was associated with increased suicidality ranging from OR = 2.88 (95% CI = 2.6-3.19) for SI to OR = 3.92 (95% CI = 3.19-4.81) for SA. In Yale-Penn, we identified multivariate gene-environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p = 1.82 × 10-7; TSNAXIP1, p = 2.13 × 10-7; CENPT, p = 2.32 × 10-7; PARD6A, p = 5.57 × 10-7) for opioid dependence (BF = 12.2), cocaine dependence (BF = 12.1), nicotine dependence (BF = 9.2), and polysubstance dependence (BF = 2.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.

Epigenomic Profiles of African-American Transthyretin Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms.

BACKGROUND: The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries (OSs) in the country. METHODS: We conducted first-ever epigenome-wide association study using the Illumina's EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs-an early disease indicator. Differential methylation across genome wide cytosine-phosphate guanine (CpG) sites was tested between carriers with and without heart disease and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication. RESULTS: Five differentially methylated sites (P≤2.1×10-8) in genes-FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 (P=1.1×10-12) were associated with heart disease. For OS, we observe 4 sites-2 sites in UBE2E3 and SEC14L5, and other 2 in intergenic regions (P≤1.8×10-7) and 3 regions overlapping SH3D21, EVA1B, LTB4R2, and CIDEB (P≤3.9×10-7). Functional protein-interaction module analysis identified ABCA1 (P=0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; P=4.1×10-24). We replicated 2 CpG sites (cg18546846 and cg06641417; P<0.05) in an external cohort of biopsy-confirmed cases of TTR (transthyretin) amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). CONCLUSIONS: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis.

Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = -0.60, p = 6.26 × 10-8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer's disease (KEGG hsa05010, q = 2.2 × 10-4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = -2.18, p = 3.34 × 10-11). Cg13139646 showed co-methylation with cg19203115 (Pearson's r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = -0.56, p = 8.6 × 10-4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry.

BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.

Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy.

BACKGROUND: Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. METHODS: Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. RESULTS: Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. CONCLUSION: With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.