Donna Werling, PhD

Assistant Professor, Genetics

Biography

PhD, University of California, Los Angeles

Contact Information

Laboratory of Genetics 5262 Genetics and Biotechnology Center Madison, WI 53706-1580 (608) 262-3113 dwerling@wisc.edu Werling Lab

Research Statement

Genetic variants contribute to risk for neurodevelopmental disorders, many of which show sex differences in their prevalence or presentation. This suggests a potential role for sex-differential biology in modulating the impact of genetic and other risk factors, such that one sex is sensitized and/or the other is protected from risk. One particularly striking example is autism spectrum disorder (ASD): Males are diagnosed with ASD at least three times more frequently than females, and this skew is one of the most consistent, yet mechanistically unexplained, features of ASD. The aim of my research is to understand the key neurobiological mechanisms involved in the etiology of ASD and other neurodevelopmental disorders, including genetic and developmental processes, with a focus on the role of sex-differential biology in modulating risk. Genome-scale analyses are especially powerful for unbiased discovery, and so my lab uses genome-wide genetics, functional genomics, and bioinformatics approaches (e.g. RNA-seq, single cell analyses, eQTLs) in human tissue and model systems to identify and characterize the mechanisms involved in sex-differential and disorder-associated neurobiology. The long-term goal of this research program is to uncover fundamental etiological pathways in both sexes that will facilitate treatment development and benefit affected individuals and their families.

Research Topics:

Autism, Bioinformatics, Brain Development, Genetic Disorders, Neural Development, Neurodevelopmental Disorders

Selected Publications

PubMed

Kim, S. W., Lee, H., Song, D. Y., Lee, G. H., Han, J. H., Lee, J. W., Byun, H. J., Son, J. H., Kim, Y. R., Lee, Y., Kim, E., Werling, D. M., Kim, S. H., Sanders, S. J., Yoo, H. J., & An, J. Y. (2025). Evaluation of familial phenotype deviation to measure the impact of de novo mutations in autism. Genome medicine, 17(1), 93. https://doi.org/10.1186/s13073-025-01532-7

Kim, S. W., Lee, H., Song, D. Y., Lee, G. H., Ji, J., Park, J. W., Han, J. H., Lee, J. W., Byun, H. J., Son, J. H., Kim, Y. R., Lee, Y., Kim, J., Jung, A., Lee, J., Kim, E., Kim, S. H., Lee, J. H., Satterstrom, F. K., Girirajan, S., … An, J. Y. (2024). Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism. Genome medicine, 16(1), 114. https://doi.org/10.1186/s13073-024-01385-6

Singh, A. P., Fromandi, M., Pimentel-Alarcón, D., Werling, D. M., Gasch, A. P., & Yu, J. J. (2024). Intrinsic Gene Expression Correlates of the Biophysically Modeled Diffusion Magnetic Resonance Imaging Signal. Biological psychiatry global open science, 5(2), 100430. https://doi.org/10.1016/j.bpsgos.2024.100430

Kissel, L. T., Pochareddy, S., An, J. Y., Sestan, N., Sanders, S. J., Wang, X., & Werling, D. M. (2024). Sex-Differential Gene Expression in Developing Human Cortex and Its Intersection With Autism Risk Pathways. Biological psychiatry global open science, 4(4), 100321. https://doi.org/10.1016/j.bpsgos.2024.100321

Kim, Y., Jeong, M., Koh, I. G., Kim, C., Lee, H., Kim, J. H., Yurko, R., Kim, I. B., Park, J., Werling, D. M., Sanders, S. J., & An, J. Y. (2024). CWAS-Plus: Estimating category-wide association of rare noncoding variation from whole-genome sequencing data with cell-type-specific functional data. medRxiv : the preprint server for health sciences, 2024.04.15.24305828. https://doi.org/10.1101/2024.04.15.24305828

Shen, M., Sirois, C. L., Guo, Y., Li, M., Dong, Q., Méndez-Albelo, N. M., Gao, Y., Khullar, S., Kissel, L., Sandoval, S. O., Wolkoff, N. E., Huang, S. X., Xu, Z., Bryan, J. E., Contractor, A. M., Korabelnikov, T., Glass, I. A., Doherty, D., Birth Defects Research Laboratory, Levine, J. E., … Zhao, X. (2023). Species-specific FMRP regulation of RACK1 is critical for prenatal cortical development. Neuron, 111(24), 3988–4005.e11. https://doi.org/10.1016/j.neuron.2023.09.014

Kissel, L. T., & Werling, D. M. (2022). Neural Transcriptomic Analysis of Sex Differences in Autism Spectrum Disorder: Current Insights and Future Directions. Biological Psychiatry, 91(1), 53–60. https://doi.org/10.1016/j.biopsych.2020.11.023

Zhang, Y., Lu, Q., Ye, Y., Huang, K., Liu, W., Wu, Y., Zhong, X., Li, B., Yu, Z., Travers, B. G., Werling, D. M., Li, J. J., & Zhao, H. (2021). SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits. Genome biology, 22(1), 262. https://doi.org/10.1186/s13059-021-02478-w

Liang, L., Fazel Darbandi, S., Pochareddy, S., Gulden, F. O., Gilson, M. C., Sheppard, B. K., Sahagun, A., An, J. Y., Werling, D. M., Rubenstein, J. L. R., Sestan, N., Bender, K. J., & Sanders, S. J. (2021). Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain. Genome medicine, 13(1), 135. https://doi.org/10.1186/s13073-021-00949-0

Werling DM, Pochareddy S, Choi J, An JY, Sheppard B, Peng M, Li Z, Dastmalchi C, Santpere G, Sousa AMM, et al. (2020). Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. Cell Reports, 31(1):107489. doi: 10.1016/j.celrep.2020.03.053. PMID: 32268104

Werling DM. (2019). Clinically Defined Subtypes of Bipolar Disorder Are Reflected in Genomic Architecture. Biological Psychiatry, 86(2):78-80. doi: 10.1016/j.biopsych.2019.05.010.

Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, Sunkin SM, Li Z, Shin Y, Zhu Y, Sousa AMM, Werling DM, Kitchen RR, Kang HJ, Pletikos M, Choi J, Muchnik S, Xu X, Wang D, Lorente-Galdos B, Liu S, Giusti-Rodríguez P, Won H, de Leeuw CA, Pardiñas AF; BrainSpan Consortium; PsychENCODE Consortium; PsychENCODE Developmental Subgroup, Hu M, Jin F, Li Y, Owen MJ, O’Donovan MC, Walters JTR, Posthuma D, Reimers MA, Levitt P, Weinberger DR, Hyde TM, Kleinman JE, Geschwind DH, Hawrylycz MJ, State MW, Sanders SJ, Sullivan PF, Gerstein MB, Lein ES, Knowles JA, Sestan N. (2018). Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science, 362(6420). pii: eaat7615. doi: 10.1126/science.aat7615.

An JY, Lin K, Zhu L, Werling DM, Dong S, Brand H, Wang HZ, Zhao X, Schwartz GB, Collins RL, et al. (2018). Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science, 14;362(6420). pii: eaat6576. doi: 10.1126/science.aat6576.

Werling DM, Brand H, An JY, Stone MR, Zhu L, Glessner JT, Collins RL, Dong S, Layer RM, Markenscoff-Papadimitriou E, Farrell A, et al. (2018). An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nature Genetics, 26;50(5):727-736. doi: 10.1038/s41588-018-0107-y.

Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S; Whole Genome Sequencing for Psychiatric Disorders (WGSPD), Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, et al. (2017). Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nature Neuroscience, 20(12):1661-1668. doi: 10.1038/s41593-017-0017-9.

Bishop SL, Farmer C, Bal V, Robinson EB, Willsey AJ, Werling DM, Havdahl KA, Sanders SJ, Thurm A. (2017). Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder. American Journal of Psychiatry, 174(6):576-585. doi: 10.1176/appi.ajp.2017.16101115.

Werling DM, Parikshak NN, Geschwind DH. (2016). Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nature Communications, 7:10717. doi: 10.1038/ncomms10717.

Werling DM. (2016). The role of sex-differential biology in risk for autism spectrum disorder. Biology of Sex Differences, 16;7:58.