Neurogenetics and Epigenetics of Loneliness

Abdalla Bowirrat; Igor Elman; Catherine A Dennen; Marjorie C Gondré-Lewis; Jean Lud Cadet; Jag Khalsa; David Baron; Diwanshu Soni; Mark S Gold; Thomas J McLaughlin; Debasis Bagchi; Eric R Braverman; Mauro Ceccanti; Panayotis K Thanos; Edward Justin Modestino; Keerthy Sunder; Nicole Jafari; Foojan Zeine; Rajendra D Badgaiyan; Debmalya Barh; Milan Makale; Kevin T Murphy; Kenneth Blum

doi:10.2147/PRBM.S423802

Neurogenetics and Epigenetics of Loneliness

Psychol Res Behav Manag. 2023 Nov 29:16:4839-4857. doi: 10.2147/PRBM.S423802. eCollection 2023.

Authors

Abdalla Bowirrat¹, Igor Elman², Catherine A Dennen³, Marjorie C Gondré-Lewis⁴, Jean Lud Cadet⁵, Jag Khalsa⁶, David Baron⁷, Diwanshu Soni⁸, Mark S Gold⁹, Thomas J McLaughlin¹⁰, Debasis Bagchi¹¹, Eric R Braverman¹², Mauro Ceccanti¹³, Panayotis K Thanos^{14

15}, Edward Justin Modestino¹⁶, Keerthy Sunder^{17

18}, Nicole Jafari^{19

20}, Foojan Zeine^{21

22}, Rajendra D Badgaiyan²³, Debmalya Barh^{24

25}, Milan Makale²⁶, Kevin T Murphy²⁷, Kenneth Blum^{1

7

10

12

18

20

24

28

29}

Affiliations

¹ Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel.
² Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, 02139, USA.
³ Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA, USA.
⁴ Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, 20059, USA.
⁵ Molecular Neuropsychiatry Research Branch, NIH National Institute on Drug Abuse, Bethesda, MD, 20892, USA.
⁶ Department of Microbiology, Immunology and Tropical Medicine, George Washington University, School of Medicine, Washington, DC, USA.
⁷ Division of Addiction Research & Education, Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA, 91766, USA.
⁸ Western University Health Sciences School of Medicine, Pomona, CA, USA.
⁹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁰ Division of Reward Deficiency Clinics, TranspliceGen Therapeutics, Inc, Austin, TX, USA.
¹¹ Department of Pharmaceutical Sciences, Texas Southern University College of Pharmacy, Houston, TX, USA.
¹² Division of Clinical Neurology, The Kenneth Blum Institute of Neurogenetics & Behavior, LLC, Austin, TX, USA.
¹³ Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, 00185, Italy.
¹⁴ 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.
¹⁵ Department of Psychology, State University of New York at Buffalo, Buffalo, NY, 14203, USA.
¹⁶ Department of Psychology, Curry College, Milton, MA, USA.
¹⁷ Karma Doctors & Karma TMS, and Suder Foundation, Palm Springs, CA, USA.
¹⁸ Department of Medicine, University of California, Riverside School of Medicine, Riverside, CA, USA.
¹⁹ Department of Human Development, California State University at Long Beach, Long Beach, CA, USA.
²⁰ Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, CA, USA.
²¹ Awareness Integration Institute, San Clemente, CA, USA.
²² Department of Health Science, California State University at Long Beach, Long Beach, CA, USA.
²³ Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY, USA.
²⁴ Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, WB, 721172, India.
²⁵ Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
²⁶ Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA, 92093-0819, USA.
²⁷ Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA.
²⁸ Department of Psychiatry, University of Vermont School of Medicine, Burlington, VA, USA.
²⁹ Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary.

Abstract

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.

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

Publication types

Review

Grants and funding

UL1 TR001409/TR/NCATS NIH HHS/United States