Neurogenetics and Epigenetics of Loneliness


Abdalla Bowirrat, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel.
Igor Elman, Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, 02139, USA.
Catherine A. Dennen, Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA.
Marjorie C. Gondré-Lewis, Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, 20059, USA.
Jean Lud Cadet, Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, 20892, USA.
Jag Khalsa, Department of Microbiology, Immunology and Tropical Medicine, George Washington University, School of Medicine, Washington, DC, USA.
David Baron, Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, 91766, USA.
Diwanshu Soni, Western University Health Sciences School of Medicine, Pomona, CA, USA.
Mark S. Gold, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Thomas J. McLaughlin, Division of Reward Deficiency Clinics, TranspliceGen Therapeutics, Inc, Austin, TX, USA.
Debasis Bagchi, Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA.
Eric R. Braverman, Division of Clinical Neurology, The Kenneth Blum Institute of Neurogenetics & Behavior, LLC, Austin, TX, USA.
Mauro Ceccanti, Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, 00185, Italy.
Panayotis K. Thanos, Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, 14203, USA.
Edward Justin Modestino, Department of Psychology, Curry College, Milton, MA, USA.
Keerthy Sunder, Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA.
Nicole Jafari, Department of Human Development, California State University at Long Beach, Long Beach, CA, USA.
Foojan Zeine, Awareness Integration Institute, San Clemente, CA, USA.
Rajendra D. Badgaiyan, Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA.
Debmalya Barh, Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, WB, 721172, India.
Milan Makale, Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA, 92093-0819, USA.
Kevin T. Murphy, Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA.
Kenneth Blum, Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel.

Document Type

Journal Article

Publication Date



Psychology research and behavior management






addiction; affective; alcohol; anti-reward; anxiety; cancer; cardiovascular; cognitive; depression; dopamine; genes; medical; motivation; reward deficiency; social isolation


Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.


Microbiology, Immunology, and Tropical Medicine