Thanks to rapid advances in resources and technology, biology has entered a dynamic, data-driven era in the 21st century. With the advent of new DNA sequencing technologies, it is a particularly exciting yet challenging time now for computational research, as more and more biological data are being generated at an ever-accelerating speed. My lab investigates the genetics of aging and human complex diseases at the interface of data science and clinical medicine through data integration, algorithm development, and software implementation of state-of-the-art methods in computational genetics and systems biology to analyze and integrate multifarious genetic and multiomic datasets.

Method development and data analysis are essential to uncovering the underlying genetic mechanisms in biomedical research. My lab specializes in both advanced genetic data analysis and novel analytical method development. Over the years, we have contributed significantly to the field by developing computational frameworks and analytical methods, including integrated post-GWAS gene prioritization techniques, rare variant-based risk gene identification methods, and protocols for genomic gene expansion analysis. Currently, our lab is actively developing Bayesian statistical methods to quantify the loss of Y chromosome (LOY), structural equation modeling (SEM) to elucidate the complexities of human aging, and Bayesian hierarchical modeling to understand congenital heart defects (CHD). Our interdisciplinary approach continues to provide new insights into genetics and disease pathogenesis, emphasizing both rigorous data analysis and methodological innovation.

Aging research is increasingly critical due to global demographic shifts, with aging populations facing heightened risks for chronic diseases such as Alzheimer's disease, cardiovascular conditions, and various forms of cancer. Understanding the genetic and molecular mechanisms underlying aging is essential for developing strategies to extend healthspan and improve quality of life. Our lab has significantly contributed to aging research through comprehensive comparative analyses of genome maintenance and DNA repair mechanisms in long-lived species like humans and naked mole rats, uncovering genetic features linked to enhanced longevity and disease resistance. We have also developed system-level approaches to identify aging-specific genetic networks and rare genetic variants that influence human longevity and episodic memory decline. By elucidating the genetic basis of extreme longevity and cognitive aging, our research aims to guide innovative therapeutic strategies and interventions to mitigate age-related decline and disease.

Human disease genetics is critical for understanding the underlying mechanisms of complex disorders and developing targeted therapies. My lab has actively contributed to this research area through innovative computational analyses, identifying novel risk genes and variants in Alzheimer's disease, schizophrenia, and 22q11.2 deletion syndrome (22q11.2DS). Our integrated post-GWAS analyses of Alzheimer's disease uncovered new genetic pathways linked to immune responses and neuronal function. In schizophrenia research, we developed computational frameworks to prioritize disease-associated genes, pinpointing those crucial for brain development and synaptic plasticity. Additionally, our studies in 22q11.2DS have identified rare coding variants that modify schizophrenia risk, emphasizing their role in postnatal cortical development. Collectively, these efforts demonstrate the importance of genetic research in decoding the biological foundations of complex diseases and enhancing patient care.

Ali A, Milman S, Weiss EF, Gao T, Napolioni V, Barzilai N, Zhang ZD, Lin JR. Genetic variants associated with age-related episodic memory decline implicate distinct memory pathologies. Alzheimers Dement. 2025, 21(1):e14379.

Lin JR, Zhao Y, Jabalameli MR, Nguyen N, Mitra J, International 22q11.DS Brain and Behavior Consortium, Swillen A, Vorstman JAS, Chow EWC, van den Bree M, Emanuel BS, Vermeesch JR, Owen MJ, Williams NM, Bassett AS, McDonald-McGinn DM, Gur RE, Bearden CE, Morrow BE, Lachman HM, Zhang ZD. Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia. Mol Psychiatry. 2023, 28(5):2071-2080.

Jabalameli MR, Zhang ZD. Unravelling genetic components of longevity. Nat Aging. 2022, 2(1):5-6.

Zhang Q, Tombline G, Ablaeva J, Zhang L, Zhou X, Smith Z, Zhao Y, Xiaoli AM, Wang Z, Lin JR, Jabalameli MR, Mitra J, Nguyen N, Vijg J, Seluanov A, Gladyshev VN, Gorbunova V, Zhang ZD. Genomic expansion of Aldh1a1 protects beavers against high metabolic aldehydes from lipid oxidation. Cell Rep. 2021, 37(6):109965.

Lin JR, Sin-Chan P, Napolioni V, Torres GG, Mitra J, Zhang Q, Jabalameli MR, Wang Z, Nguyen N, Gao T, Regeneron Genetics Center, Laudes M, Görg S, Franke A, Nebel A, Greicius MD, Atzmon G, Ye K, Gorbunova V, Ladiges WC, Shuldiner AR, Niedernhofer LJ, Robbins PD, Milman S, Suh Y, Vijg J, Barzilai N, Zhang ZD. Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nat Aging. 2021, 1(9):783-794.

Oh S, Shao J, Mitra J, Xiong F, D'Antonio M, Wang R, Garcia-Bassets I, Ma Q, Zhu X, Lee JH, Nair SJ, Yang F, Ohgi K, Frazer KA, Zhang ZD, Li W, Rosenfeld MG. Enhancer release and retargeting activates disease-susceptibility genes. Nature. 2021, 595(7869):735-740.

Zhang ZD, Milman S, Lin JR, Wierbowski S, Yu H, Barzilai N, Gorbunova V, Ladiges WC, Niedernhofer LJ, Suh Y, Robbins PD, Vijg J. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab. 2020, 2(8):663-672.