Frank Wendt, PhD
Research & Publications
Biography
News
Research Summary
My research embodies both basic and applied sciences to understand the genetics of complex traits and how race, ethnicity, and genetically determined ancestry influence these findings. My overall research goal is to understand the shared genetic influence for mental health, psychopathology, and behavior. This interest in trait relationships is typically anchored around the internalizing spectrum of disorders (major depressive disorder, generalized anxiety disorder, posttraumatic stress disorder) and trans-diagnostic internalizing domains (neuroticism).
Extensive Research Description
As a first-generation college student, I was not exposed to academic research until college. One morning in autumn of 2010, I bundled up in my warmest clothing and snapped crampons onto my boots for my first site visit to the northern facing slopes of the Appalachian Mountains to collect ice cores from caves frozen for >10 months/year. Mentored by Dr. Corien Bakermans at Penn State University (PSU), I amplified 16S rRNA of archaea from ice cores for comparison to Antarctic cores. Though my excitement for field work faded, I mastered primer design and polymerase chain reaction which were essential skills for my successful research career. In 2011, I joined Dr. Mitchell Holland’s group at PSU to develop human genetics bench skills related to short tandem repeat (STR) assay development. We collaborated with the start-up company IntegenX to alpha test an instrument for rapid amplification (~90 minutes) and size separation of STR amplicons.
In 2014, I moved to Texas for doctoral training with Dr. Bruce Budowle at University of North Texas Health Science Center (UNTHSC). I developed machine learning models predicting response to the synthetic opioid agonist tramadol using a pathway-driven approach. In collaboration with Dr. Antti Sajantila (University of Helsinki), I (i) characterized the population genetic diversity of pharmacogenomic (PGx) SNPs, (ii) tested for shared inheritance patterns within and between genes, and (iii) used sequence data from CYP2D6, UGT2B7, ABCB1, OPRM1, and COMT for machine learning prediction of tramadol:primary metabolite ratio. Tramadol metabolism was best predicted with a five-gene model with highest accuracy estimates using 16 SNPs. My dissertation work formed the foundation for my interest in complex traits and the concepts of polygenicity (the additive effects of many loci on a phenotype) and pleiotropy (when multiple traits share liability loci).
My major scientific contribution outside of my dissertation was in STR population genetics. In collaboration with Drs. Sree Kanthaswamy (Arizona State University), Nicole Novroski (University of Toronto), Katherine Gettings (NIST), and Bruce Budowle (UNTHSC), I (i) characterized STR sequence diversity in US populations, (ii) expanded the STR allele identification tool (STRait Razor software) to assign STR genotypes from massively parallel sequencing data, and (iii) published the first studies of STR and microhaplotype (e.g., STR+SNP, SNP+SNP) variation in the Yavapai and Chachapoyas populations. These studies expanded allele frequency databases at Yale, the Federal Bureau of Investigation, and NIST.
To expand my interest in polygenic prediction of complex traits, I joined Yale for rigorous training in the genetics of psychiatric disorders. Under the mentorship of Dr. Renato Polimanti, I have coauthored >25 manuscripts and obtained an NRSA F32 fellowship through NIMH. As a fellow, I investigate sex differences in genetic liability for psychiatric disorders. Among the studies completed, I lead a study of sex-stratified gene-by-environment interactions influencing genetic risk for suicidality. We identified relationships between (i) physical violence and male suicidality genetic risk and (ii) post-trauma avoidance and upset feelings and female suicidality genetic risk. I also established analytic pipelines to understand trait relationships including (i) polygenic architecture, (ii) causal inference, (iii) latent genetic factors, (iv) PGx risk factors, and (v) cross-population effects. In response to COVID-19, I volunteered my expertise to studies of host genetic liability resulting in collaborations with the COVID-19 Host Genetics Initiative and the Million Veteran Program (MVP) COVID-19 PGx Work Group. I currently lead MVP initiatives to understand genetic and environmental risks for Gulf War Veterans Illness and the effects of cryptic genetic heterogeneity within ancestry strata on gene discovery of complex traits.
Though currently focused on mental health, I remain actively involved in forensic science research. I am currently leading/supervising several projects to understand biases in DNA mixture match statistics as a consequence of the growing prevalence of admixture in the United States and Canada. These studies aim to reduce prejudicial reporting of DNA "matches" in the presence/absence of contributors from low genetic diversity populations.
Coauthors
Selected Publications
- Multivariate genome-wide analysis of education, socioeconomic status and brain phenome.Wendt FR, Pathak GA, Lencz T, Krystal JH, Gelernter J, Polimanti R. Multivariate genome-wide analysis of education, socioeconomic status and brain phenome. Nature Human Behaviour 2021, 5: 482-496. PMID: 33349686, PMCID: PMC8068566, DOI: 10.1038/s41562-020-00980-y.
- Characterizing the effect of background selection on the polygenicity of brain-related traits.Wendt FR, Pathak GA, Overstreet C, Tylee DS, Gelernter J, Atkinson EG, Polimanti R. Characterizing the effect of background selection on the polygenicity of brain-related traits. Genomics 2021, 113: 111-119. PMID: 33278486, PMCID: PMC7855394, DOI: 10.1016/j.ygeno.2020.11.032.
- Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use.Wendt FR, Koller D, Pathak GA, Jacoby D, Miller EJ, Polimanti R. Biobank Scale Pharmacogenomics Informs the Genetic Underpinnings of Simvastatin Use. Clinical Pharmacology And Therapeutics 2021, 110: 777-785. PMID: 33837531, PMCID: PMC8376807, DOI: 10.1002/cpt.2260.
- Polygenic risk for autism spectrum disorder associates with anger recognition in a neurodevelopment-focused phenome-wide scan of unaffected youths from a population-based cohort.Wendt FR, Carvalho CM, Pathak GA, Gelernter J, Polimanti R. Polygenic risk for autism spectrum disorder associates with anger recognition in a neurodevelopment-focused phenome-wide scan of unaffected youths from a population-based cohort. PLoS Genetics 2020, 16: e1009036. PMID: 32941431, PMCID: PMC7523983, DOI: 10.1371/journal.pgen.1009036.
- Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.Wendt FR, Pathak GA, Levey DF, Nuñez YZ, Overstreet C, Tyrrell C, Adhikari K, De Angelis F, Tylee DS, Goswami A, Krystal JH, Abdallah CG, Stein MB, Kranzler HR, Gelernter J, Polimanti R. Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality. Neurobiology Of Stress 2021, 14: 100309. PMID: 33665242, PMCID: PMC7905234, DOI: 10.1016/j.ynstr.2021.100309.
- Potential causal effect of posttraumatic stress disorder on alcohol use disorder and alcohol consumption in individuals of European descent: A Mendelian Randomization Study.Bountress KE, Wendt F, Bustamante D, Agrawal A, Webb B, Gillespie N, Edenberg H, Sheerin C, Johnson E, Polimanti R, Amstadter A. Potential causal effect of posttraumatic stress disorder on alcohol use disorder and alcohol consumption in individuals of European descent: A Mendelian Randomization Study. Alcoholism, Clinical And Experimental Research 2021, 45: 1616-1623. PMID: 34120358, PMCID: PMC8429238, DOI: 10.1111/acer.14649.
- Attachment Style Moderates Polygenic Risk for Posttraumatic Stress in United States Military Veterans: Results From the National Health and Resilience in Veterans Study.Tamman AJF, Wendt FR, Pathak GA, Krystal JH, Montalvo-Ortiz JL, Southwick SM, Sippel LM, Gelernter J, Polimanti R, Pietrzak RH. Attachment Style Moderates Polygenic Risk for Posttraumatic Stress in United States Military Veterans: Results From the National Health and Resilience in Veterans Study. Biological Psychiatry 2021, 89: 878-887. PMID: 33276944, DOI: 10.1016/j.biopsych.2020.09.018.
- Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.Stein MB, Levey DF, Cheng Z, Wendt FR, Harrington K, Pathak GA, Cho K, Quaden R, Radhakrishnan K, Girgenti MJ, Ho YA, Posner D, Aslan M, Duman RS, Zhao H, Polimanti R, Concato J, Gelernter J. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nature Genetics 2021, 53: 174-184. PMID: 33510476, PMCID: PMC7972521, DOI: 10.1038/s41588-020-00767-x.
- A large-scale genome-wide association study meta-analysis of cannabis use disorder.Johnson EC, Demontis D, Thorgeirsson TE, Walters RK, Polimanti R, Hatoum AS, Sanchez-Roige S, Paul SE, Wendt FR, Clarke TK, Lai D, Reginsson GW, Zhou H, He J, Baranger DAA, Gudbjartsson DF, Wedow R, Adkins DE, Adkins AE, Alexander J, Bacanu SA, Bigdeli TB, Boden J, Brown SA, Bucholz KK, Bybjerg-Grauholm J, Corley RP, Degenhardt L, Dick DM, Domingue BW, Fox L, Goate AM, Gordon SD, Hack LM, Hancock DB, Hartz SM, Hickie IB, Hougaard DM, Krauter K, Lind PA, McClintick JN, McQueen MB, Meyers JL, Montgomery GW, Mors O, Mortensen PB, Nordentoft M, Pearson JF, Peterson RE, Reynolds MD, Rice JP, Runarsdottir V, Saccone NL, Sherva R, Silberg JL, Tarter RE, Tyrfingsson T, Wall TL, Webb BT, Werge T, Wetherill L, Wright MJ, Zellers S, Adams MJ, Bierut LJ, Boardman JD, Copeland WE, Farrer LA, Foroud TM, Gillespie NA, Grucza RA, Harris KM, Heath AC, Hesselbrock V, Hewitt JK, Hopfer CJ, Horwood J, Iacono WG, Johnson EO, Kendler KS, Kennedy MA, Kranzler HR, Madden PAF, Maes HH, Maher BS, Martin NG, McGue M, McIntosh AM, Medland SE, Nelson EC, Porjesz B, Riley BP, Stallings MC, Vanyukov MM, Vrieze S, Davis LK, Bogdan R, Gelernter J, Edenberg HJ, Stefansson K, Børglum AD, Agrawal A. A large-scale genome-wide association study meta-analysis of cannabis use disorder. The Lancet. Psychiatry 2020, 7: 1032-1045. PMID: 33096046, PMCID: PMC7674631, DOI: 10.1016/S2215-0366(20)30339-4.
- Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality.Polimanti R, Levey DF, Pathak GA, Wendt FR, Nunez YZ, Ursano RJ, Kessler RC, Kranzler HR, Stein MB, Gelernter J. Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality. Translational Psychiatry 2021, 11: 34. PMID: 33431810, PMCID: PMC7801457, DOI: 10.1038/s41398-020-01153-1.
- Epigenomic Profiles of African-American Transthyretin Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms.Pathak GA, Wendt FR, De Lillo A, Nunez YZ, Goswami A, De Angelis F, Fuciarelli M, Kranzler HR, Gelernter J, Polimanti R. Epigenomic Profiles of African-American Transthyretin Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms. Circulation. Genomic And Precision Medicine 2021, 14: e003011. PMID: 33428857, PMCID: PMC7887108, DOI: 10.1161/CIRCGEN.120.003011.
- Investigating Causality Between Blood Metabolites and Emotional and Behavioral Responses to Traumatic Stress: a Mendelian Randomization Study.Carvalho CM, Wendt FR, Stein DJ, Stein MB, Gelernter J, Belangero SI, Polimanti R. Investigating Causality Between Blood Metabolites and Emotional and Behavioral Responses to Traumatic Stress: a Mendelian Randomization Study. Molecular Neurobiology 2020, 57: 1542-1552. PMID: 31786776, DOI: 10.1007/s12035-019-01823-2.
- Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions.Levey DF, Stein MB, Wendt FR, Pathak GA, Zhou H, Aslan M, Quaden R, Harrington KM, Nuñez YZ, Overstreet C, Radhakrishnan K, Sanacora G, McIntosh AM, Shi J, Shringarpure SS, Concato J, Polimanti R, Gelernter J. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nature Neuroscience 2021, 24: 954-963. PMID: 34045744, PMCID: PMC8404304, DOI: 10.1038/s41593-021-00860-2.
- Polygenic risk for traumatic loss-related PTSD in US military veterans: Protective effect of secure attachment style.Asch RH, Esterlis I, Wendt FR, Kachadourian L, Southwick SM, Gelernter J, Polimanti R, Pietrzak RH. Polygenic risk for traumatic loss-related PTSD in US military veterans: Protective effect of secure attachment style. The World Journal Of Biological Psychiatry : The Official Journal Of The World Federation Of Societies Of Biological Psychiatry 2021, 22: 792-799. PMID: 33821766, PMCID: PMC8925016, DOI: 10.1080/15622975.2021.1907721.