Renato Polimanti

Yale University | YU · Department of Psychiatry

Self-domestication could contribute to shaping the biology of human brain and consequently the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spectrum disorde...

Background: Alcohol use disorder is a public health problem, especially among US veterans. This study examined the nature and predictors of 10-year trajectories of alcohol consumption in US veterans. Methods: Data were analyzed from the 2011-2021 National Health and Resilience in Veterans Study, a nationally representative, longitudinal study of...

Leveraging genome-wide association statistics generated from a large study of amyotrophic lateral sclerosis (ALS; 29,612 cases and 122,656 controls) and UK Biobank (UKB; 4,024 phenotypes, up to 361,194 participants), we conducted a phe-nome-wide analysis of ALS genetic liability and identified 46 genetically correlated traits, such as fluid intelli...

Aims: We performed a latent class analysis (LCA) in a sample ascertained for addiction phenotypes to investigate cocaine use disorder (CoUD) subgroups related to polysubstance addiction (PSA) patterns and characterized their differences with respect to psychiatric and somatic comorbidities. Design: Cross-sectional study Setting: United States Parti...

Importance Endometriosis is a common chronic gynecologic pathology with a large negative impact on women’s health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety. Objective To investigate whether pleiotropy contributes to the association of endometriosis wi...

Emotion recognition, particularly of anger expressions, has a crucial adaptive and social value for human beings. Similar to other human traits, emotion recognition is highly variable among individuals and has been shown to be altered in several mental disorders. There is evidence that emotion recognition is heritable and, thus, potentially influen...

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functio...

Genetic variants in the third intron of the PRDM6 gene have been associated with blood pressure traits in multiple genome-wide association studies (GWAS). By combining fine mapping, massive-ly parallel reporter assays, and gene editing we identified the causal variants for hypertension as super-enhancers that drive the expression of PRDM6 and are p...

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990–1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA’s Cooperative Studies Program 2006/Million V...

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities of African descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has al...

When present in coding regions, tandem repeats (TRs) may have large effects on protein structure and function contributing to health and disease. We use a family-based design to identify de novo TRs and assess their impact at the population level in 148,607 European ancestry participants from the UK Biobank. The 427 loci with de novo TR mutations a...

The widespread comorbidity among psychiatric disorders demonstrated in epidemiological studies1–5 is mirrored by non-zero, positive genetic correlations from large-scale genetic studies6–10. To identify shared biological processes underpinning this observed phenotypic and genetic covariance and enhance molecular characterization of general psychiat...

To investigate assortative mating (AM), participation bias, and socioeconomic status (SES) with respect to the genetics of behavioral and psychiatric traits, we analyzed gametic phase disequilibrium (GPD), within-spouses and within-siblings polygenic risk score (PRS) correlation, performing a SES conditional analysis. We observed genetic signatures...

Background: Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior. Methods: This study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population...

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has alw...

Background Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with sig...

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functio...

We hypothesized that overall autozygosity is decreasing over generational time. In this report, we present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us and the Million Veteran Program, N=82,474 and 622,497, respectively) and one from the UK (UK Biobank, N=380,899). Our result...

Multiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We test for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or t...

Importance: Alcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc). Objectives: To identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol...

Self-domestication could play an important role in contributing to shape the biology of human brain and the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spe...

Leveraging genome-wide association statistics generated from a large study of amyotrophic lateral sclerosis (ALS; 29,612 cases and 122,656 controls) and UK Biobank (UKB; 4,024 phenotypes, up to 361,194 participants), we conducted a phenome-wide genetic correlation analysis of ALS and identified 46 genetically-correlated traits, such as fluid intell...

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We conducted genome-wide association studies of short (less than 6 hours) and long (more than 9 hours) sleep duration in adults of European, African, East Asian, and admixed-American ancestry from UK Biobank and the Million Veteran Program. In...

The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK...

Background The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specif...

Background Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction this relationship. Methods Linkage Disequilibrium Score Regression and two-sample Mendelian r...

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically cor...

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 studies with 88,316 MD cases and 902,757 controls to previously reported data from individuals of European ancestry. This includes samples of African (36% of effect...

Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size t...

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in SARS-CoV-2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Ve...

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with...

Background Due to its large impact on human health, socio-economic status (SES) could at least partially influence the established association between obesity and coronavirus disease 2019 (COVID-19) severity. To estimate the independent effect of body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (M...

Telomeres are short tandem repeats of “TTAGGG” that protect the chromosome ends from deterioration or fusion of chromosomes. Their repeat length shortens with cell division acting as a biomarker of cellular aging. Traumatic stress events during adulthood or childhood have been associated with posttraumatic stress disorder (PTSD) and short leukocyte...

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 s...

Importance Alcohol genome-wide association studies (GWAS) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc). Objective Identify MaxAlc loci and elucidate the genetic architecture across alcohol traits. Design The MaxAlc GWAS was...

Daniel Tylee gave an oral presentation characterizing results of an investigation of genetic correlations and causal inference effects (i.e., Mendelian randomization) between a large set of psychiatric and immune-related phenotypes, including allergic, autoimmune, inflammatory disorders, as well as a set of hypothesized confounding phenotypes (e.g....

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide as...

The widespread comorbidity among psychiatric disorders (PDs) demonstrated in epidemiological studies is mirrored by non-zero, positive genetic correlations from large scale genetic studies. We employed several strategies to uncover pleiotropic SNPs, genes and biological pathways underlying this genetic covariance. First, we conducted cross-trait me...

Background The integration of multi-omics information (e.g., epigenetics and transcriptomics) can be useful for interpreting findings from genome-wide association studies (GWAS). It has additionally been suggested that multi-omics may aid in novel variant discovery, thus circumventing the need to increase GWAS sample sizes. We tested whether incorp...

Background Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWAS). Meth...

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire (“MHQ responders”). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB...

Background The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed among affected individuals. To understand the dynamics underlying PTSD-CAD comorbidity, we conducted a genetically-informed causal inference analysis using large-scale genome-wide associa...

Background The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specif...

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTS...

Background Antipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsych...

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-Am...

Background Posttraumatic stress disorder (PTSD) is triggered by environmental stressors. Empathy may predispose an individual to respond to life events differently if high empathizers are emotionally more sensitive to trauma. For the first time, we test this hypothesis using genetic information. Methods We applied polygenic scoring (PGS) to invest...

Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and...

Importance: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. Objective: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We test...

Background Tandem repeats (TRs) are a major source of variation in the human genome under-investigated by large-scale genetic studies. When present in coding regions, TRs may have large effects on protein structure and function contributing to health and disease. Methods In a family-based design of 39 European ancestry trios from the UK Biobank (U...

We conducted a comprehensive genome-wide investigation of hearing loss (HL) in 748,668 adult participants of the UK Biobank, the Nurses Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program. We identified 54 risk loci and characterized HL polygenic architecture, exploring sex differences, polygenic ris...

The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic change over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). The MVP was divided in...

Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,...

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...

Risk factors and long-term consequences of COVID-19 infection are unclear but can be investigated with large-scale genomic data. To distinguish correlation from causation, we performed in-silico analyses of three COVID-19 outcomes (N > 1,000,000). We show genetic correlation and putative causality with depressive symptoms, metformin use (genetic ca...