Frank Wendt

University of Toronto | U of T · Department of Anthropology

Socioeconomic status (SES) and education (EDU) are phenotypically associated with psychiatric disorders and behaviours. It remains unclear how these associations influence genetic risk for psychopathology, psychosocial factors and EDU and/or SES (EDU/SES) individually. Using information from >1 million individuals, we conditioned the genetic risk f...

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...

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...

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...

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...

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...

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, t...

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 disord...

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...

Importance Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants This genome-wide association study included 633 778 US military veterans with and without SITB, as ide...

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 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...

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...

Probabilistic genotyping permits a comparison of forensic evidence given hypotheses regarding the origin of observed short tandem repeat alleles in a mixed DNA profile. Using the publicly available R package forensim, it has been proposed that mixtures with non-contributors from low genetic diversity populations are more likely to be mistakenly ide...

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...

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...

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...

Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 20...

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....

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...

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...

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...

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...

Background: Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. Methods: 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)...

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 trait...

Background Machine learning (ML) models are beginning to proliferate in psychiatry, however machine learning models in psychiatric genetics have not always accounted for ancestry. Using an empirical example of a proposed genetic test for OUD, and exploring a similar test for tobacco dependence and a simulated binary phenotype, we show that genetic...

Background Posttraumatic stress disorder (PTSD) develops consequent to complex gene-environment interactions beyond the precipitating trauma. To date, however, no known study has used a prospective design to examine how polygenic risk scores (PRS) interact with social-environmental factors such as attachment style to predict PTSD development. Meth...

There is a well-known association of traumatic experiences and posttraumatic stress disorder (PTSD) with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand the genetic underpinnings of this complex relationship, we investigated genome-wide datasets...

Copper is a metal that is commonly found in many evidence types, such as weapons, and household items, that are often retrieved from crime scenes. We used copper and brass sheets, cartridge cases, and metal décor items as substrates for deposition of blood to study inhibition induced by metals. Another objective was to compare the efficiency of STR...

Angiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact...

Evidence of how human evolution shaped the polygenicity of human traits and diseases has been extensively studied in populations of European descent. However, limited information is currently available about its impact on other ancestry groups. Here, we investigated how different evolutionary processes affected the common variant heritability of tr...

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 at the genetic level. Methods We applied polygenic scoring (PGS) to investigate...

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, s...

Background: Transthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR)....

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...

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanis...

Background Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants tha...

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,...

Background Obesity has been associated with more severe clinical manifestations of coronavirus disease 2019 (COVID-19). However, this association can be affected by many correlates of these traits. Due to its large impact on human health, socioeconomic status (SES) could at least partially influence the association between obesity and COVID-19 seve...

The goals of this study were to (a) ascertain human identity capabilities of DNA obtained from latent fingerprints that have been first environmentally insulted and then developed by the deposition of a columnar thin film (CTF), and (b) to determine if the CTF process and material are detrimental to single nucleotide polymorphism (SNP) analysis. Fi...

Background Posttraumatic Stress Disorder (PTSD) often co-occurs with increased alcohol consumption (AC) and alcohol use disorder (AUD), however it is unknown whether the same etiologic influences underlying PTSD-AUD comorbidity are those underlying PTSD and AC. Methods This study used large-scale genome wide association study (GWAS) data to test i...

Microbes inhabit different anatomical sites of the human body including oral cavity, gut, and skin. A growing literature highlights how microbiome variation is associated with human health and disease. There is strong evidence of bidirectional communication between gut and brain mediated by neurotransmitters and microbial metabolites. Here, we revi...

To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European, and Middle Eastern participants of UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping varia...

Studying drug‐metabolizing enzymes, encoded by pharmacogenes, may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, pharmacogenes could not be studied at biobank scale. In 7,649 unrelated African‐ancestry (AFR) and 326,214 unrelated European‐ancestry (EUR) participants from the UK Biobank, we...

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. While telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulato...

Objectives To examine whether attachment style moderates the relationship between polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) re-experiencing (PTSDREX) symptoms and the severity of and positive screen for traumatic loss-related PTSD. Methods Data were analyzed from 631 U.S. veterans who endorsed “unexpected death of a love...

Posttraumatic stress disorder (PTSD) is a complex mental disorder afflicting approximately 7% of the population. The diverse number of traumatic events and the wide array of symptom combinations leading to PTSD diagnosis contribute substantial heterogeneity to studies of the disorder. Genomic and complimentary-omic investigations have rapidly incre...