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.

Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation.

Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.

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.

Genetically Informed Study Highlights Income-Independent Effect of Schizophrenia Liability on Mental and Physical Health.

BACKGROUND AND HYPOTHESIS: Individuals with schizophrenia (SCZ) suffer from comorbidities that substantially reduce their life expectancy. Socioeconomic inequalities could contribute to many of the negative health outcomes associated with SCZ. STUDY DESIGN: We investigated genome-wide datasets related to SCZ (52 017 cases and 75 889 controls) from the Psychiatric Genomics Consortium, household income (HI; N = 361 687) from UK Biobank, and 2202 medical endpoints assessed in up to 342 499 FinnGen participants. A phenome-wide genetic correlation analysis of SCZ and HI was performed, also assessing whether SCZ genetic correlations were influenced by the HI effect on SCZ. Additionally, SCZ and HI direct effects on medical endpoints were estimated using multivariable Mendelian randomization (MR). STUDY RESULTS: SCZ and HI showed overlapping genetic correlations with 70 traits (P < 2.89 × 10-5), including mental health, substance use, gastrointestinal illnesses, reproductive outcomes, liver diseases, respiratory problems, and musculoskeletal phenotypes. SCZ genetic correlations with these traits were not affected by the HI effect on SCZ. Considering Bonferroni multiple testing correction (P < 7.14 × 10-4), MR analysis indicated that SCZ and HI may affect medical abortion (SCZ OR = 1.07; HI OR = 0.78), panic disorder (SCZ OR = 1.20; HI OR = 0.60), personality disorders (SCZ OR = 1.31; HI OR = 0.67), substance use (SCZ OR = 1.2; HI OR = 0.68), and adjustment disorders (SCZ OR = 1.18; HI OR = 0.78). Multivariable MR analysis confirmed that SCZ effects on these outcomes were independent of HI. CONCLUSIONS: The effect of SCZ genetic liability on mental and physical health may not be strongly affected by socioeconomic differences. This suggests that SCZ-specific strategies are needed to reduce negative health outcomes affecting patients and high-risk individuals.

The impact of assortative mating, participation bias and socioeconomic status on the polygenic risk of behavioural and psychiatric traits.

To investigate assortative mating (AM), participation bias and socioeconomic status (SES) with respect to the genetics of behavioural and psychiatric traits, we estimated AM signatures using gametic phase disequilibrium and within-spouses and within-siblings polygenic risk score correlation analyses, also performing a SES conditional analysis. The cross-method meta-analysis identified AM genetic signatures for multiple alcohol-related phenotypes, bipolar disorder, major depressive disorder, schizophrenia and Tourette syndrome. Here, after SES conditioning, we observed changes in the AM genetic signatures for maximum habitual alcohol intake, frequency of drinking alcohol and Tourette syndrome. We also observed significant gametic phase disequilibrium differences between UK Biobank mental health questionnaire responders versus non-responders for major depressive disorder and alcohol use disorder. These results highlight the impact of AM, participation bias and SES on the polygenic risk of behavioural and psychiatric traits, particularly in alcohol-related traits.

Sex differences in the associations of socioeconomic factors and cognitive performance with family history of Alzheimer's disease.

INTRODUCTION: While higher socioeconomic factors (SEF) and cognitive performance (CP) have been associated with reduced Alzheimer's disease (AD) risk, recent evidence highlighted that these factors may have opposite effects on family history of AD (FHAD). METHODS: Leveraging data from the UK Biobank (N=448,100) and the All of Us Research Program (N=240,319), we applied generalized linear regression models, polygenic risk scoring (PRS), and one-sample Mendelian randomization (MR) to test the sex-specific SEF and CP associations with AD and FHAD. RESULTS: Observational and genetically informed analyses highlighted that higher SEF and CP were associated with reduced AD and sibling-FHAD, while these factors were associated with increased parent-FHAD. We also observed that population minorities may present different patterns with respect to sibling-FHAD vs. parent-FHAD. Sex differences in FHAD associations were identified in ancestry-specific and SEF PRS and MR results. DISCUSSION: This study contributes to understanding the sex-specific relationships linking SEF and CP to FHAD, highlighting the potential role of reporting, recall, and surviving-related dynamics.

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.

Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants.

We leveraged information from more than 1.2 million participants to investigate the genetics of anxiety disorders across five continental ancestral groups. Ancestry-specific and cross-ancestry genome-wide association studies identified 51 anxiety-associated loci, 39 of which are novel. Additionally, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, Admixed-American, and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, the cerebral cortex, the cerebellum, the metencephalon, the entorhinal cortex, and the brain stem. Transcriptome- and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. We also observed global and local genetic correlations with depression, schizophrenia, and bipolar disorder and putative causal relationships with several physical health conditions. Overall, this study expands the knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome.

Background: Previous epidemiological research has linked posttraumatic stress disorder (PTSD) with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records provide an opportunity to overcome clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex. Methods: PTSD was defined among biobank participants (N = 145,959) in 3 major healthcare systems using 2 ICD code-based definitions: broad (≥1 PTSD or acute stress codes vs. 0; n cases = 16,706) and narrow (≥2 PTSD codes vs. 0; n cases = 3325). Using a phenome-wide association study design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified phenome-wide association study analyses including a sex × diagnosis interaction term in each logistic regression. Results: A substantial number of phecodes were significantly associated with PTSDNarrow (61%) and PTSDBroad (83%). While the strongest associations were shared between the 2 definitions, PTSDBroad captured 334 additional phecodes not significantly associated with PTSDNarrow and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed in that PTSDBroad was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients. Conclusions: This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using electronic health records.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that some people develop following a traumatic event. In addition to mental symptoms, PTSD can impact human health in ways other ways; for example, there are many known conditions that co-occur with PTSD, such as cardiovascular conditions. In this study, we set out to understand the breadth and degree to which PTSD co-occurs with medical outcomes in a sample of over 146,000 patients across 3 large medical systems. We found that both narrowly and broadly defined PTSD diagnosis co-occurred with hundreds of medical conditions, and the strongest associations were with other psychiatric disorders, respiratory conditions (asthma, GERD), sleep-related conditions, and pain. These results provide insights into future genetic studies of PTSD in large-scale biobanks and deepen our understanding of the complex needs of patients with PTSD.

Longitudinal Patterns of Multimorbidity in Gulf War Era Veterans With and Without Gulf War Illness.

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository (n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging.

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.

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.