Research Article
Open access
Published on 26 July 2024
Download pdf
Gao,Y.;Sang,C.;Shen,G.;Xu,Y. (2024). Discovery of genes prominent in ADHD and SUDs: A meta-analysis and review. Theoretical and Natural Science,45,102-112.
Export citation

Discovery of genes prominent in ADHD and SUDs: A meta-analysis and review

Yaqing Gao *,1, Chen Sang 2, Guotai Shen 3, Yuan Xu 4
  • 1 Changzhi Medical College
  • 2 Arizona State University
  • 3 Northeastern University
  • 4 Zhengzhou No.47 Middle School

* Author to whom correspondence should be addressed.

https://doi.org/10.54254/2753-8818/45/20240532

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric condition characterized by symptoms of inattention, hyperactivity, and impulsivity, with a high prevalence among school-aged children. Substance Use Disorders (SUDs) are often comorbid with ADHD, yet the genetic linkages between these two disorders are not well understood. This study aims to fill the research gap by performing a meta-analysis on seven existing Genome-Wide Association Studies (GWAS) datasets using PLINK 1.9 software to explore the genetic commonalities between ADHD and SUDs. Prior studies have identified separate genetic markers for each disorder, but comprehensive research examining the overlap between these two conditions remains scarce. Our meta-analysis identified multiple significant Single Nucleotide Polymorphisms (SNPs) and associated genes that are relevant to both ADHD and SUDs. These genes exhibited significant p-values, underlining their potential role in the comorbid genetic landscape of these conditions. The findings of this study provide novel insights into the shared genetic etiology of ADHD and SUDs and suggest promising avenues for future research and potential therapeutic interventions.

Keywords

ADHD, GWAS, SUDs, Genetic intersections, Catecholamine system

[1]. Maxwell, A. (2011). Are some individuals diagnosed with ADHD prone to alcohol abuse? Journal of Attention Disorders, 17(2), 98–101. https://doi.org/10.1177/1087054711427400 

[2]. Thomas, R., Sanders, S., Doust, J., Beller, E., & Glasziou, P. (2015). Prevalence of attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. Pediatrics, 135(4). https://doi.org/10.1542/peds.2014-3482 

[3]. Biederman, Joseph. (2005). Attention-deficit/hyperactivity disorder: A selective overview. Biological Psychiatry, 57(11), 1215–1220. https://doi.org/10.1016/j.biopsych.2004.10.020 

[4]. Fayyad, J., Sampson, N. A., Hwang, I., Adamowski, T., Aguilar-Gaxiola, S., Al-Hamzawi, A., Andrade, L. H., Borges, G., de Girolamo, G., Florescu, S., Gureje, O., Haro, J. M., Hu, C., Karam, E. G., Lee, S., Navarro-Mateu, F., O’Neill, S., Pennell, B.-E., Piazza, M., … Kessler, R. C. (2016). The descriptive epidemiology of DSM-IV ADULT ADHD in the World Health Organization World Mental Health Surveys. ADHD Attention Deficit and Hyperactivity Disorders, 9(1), 47–65. https://doi.org/10.1007/s12402-016-0208-3 

[5]. Hao, W., & Lu, L. (2018). In Jing Shen Bing Xue = psychiatry (9th ed., pp. 125–149). essay, Ren min wei sheng chu ban she. 

[6]. Dalsgaard, S., Mortensen, P. B., Frydenberg, M., & Thomsen, P. H. (2013). Long-term criminal outcome of children with attention deficit hyperactivity disorder. Criminal Behaviour and Mental Health, 23(2), 86–98. https://doi.org/10.1002/cbm.1860 

[7]. Dalsgaard, S., Østergaard, S. D., Leckman, J. F., Mortensen, P. B., & Pedersen, M. G. (2015). Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: A nationwide cohort study. The Lancet, 385(9983), 2190–2196. https://doi.org/10.1016/s0140-6736(14)61684-6 

[8]. Wilens, T. E. (2006). Attention deficit hyperactivity disorder and substance use disorders. American Journal of Psychiatry, 163(12), 2059–2063. https://doi.org/10.1176/ajp.2006.163.12.2059 

[9]. Dalsgaard, S., Mortensen, P. B., Frydenberg, M., & Thomsen, P. H. (2014). ADHD, stimulant treatment in childhood and subsequent substance abuse in adulthood — a naturalistic long-term follow-up study. Addictive Behaviors, 39(1), 325–328. https://doi.org/10.1016/j.addbeh.2013.09.002 

[10]. Molina, B. S. G., Howard, A. L., Swanson, J. M., Stehli, A., Mitchell, J. T., Kennedy, T. M., Epstein, J. N., Arnold, L. E., Hechtman, L., Vitiello, B., & Hoza, B. (2018). Substance use through adolescence into early adulthood after childhood-diagnosed ADHD: Findings from the MTA Longitudinal Study. Journal of Child Psychology and Psychiatry, 59(6), 692–702. https://doi.org/10.1111/jcpp.12855 

[11]. Wimberley, T., Agerbo, E., Horsdal, H. T., Ottosen, C., Brikell, I., Als, T. D., Demontis, D., Børglum, A. D., Nordentoft, M., Mors, O., Werge, T., Hougaard, D., Bybjerg‐Grauholm, J., Hansen, M. B., Mortensen, P. B., Thapar, A., Riglin, L., Langley, K., & Dalsgaard, S. (2020). Genetic liability to ADHD and substance use disorders in individuals with ADHD. Addiction, 115(7), 1368–1377. https://doi.org/10.1111/add.14910 

[12]. Huntley, Z., & Young, S. (2012). Alcohol and substance use history among ADHD adults. Journal of Attention Disorders, 18(1), 82–90. https://doi.org/10.1177/1087054712446171

[13]. Faraone, S. V., Wilens, T. E., Petty, C., Antshel, K., Spencer, T., & Biederman, J. (2007). Substance use among ADHD adults: Implications of late onset and subthreshold diagnoses. American Journal on Addictions, 16(s1), 24–34. https://doi.org/10.1080/10550490601082767

[14]. Griswold, M. G., Fullman, N., Hawley, C., Arian, N., Zimsen, S. R., Tymeson, H. D., Venkateswaran, V., Tapp, A. D., Forouzanfar, M. H., Salama, J. S., Abate, K. H., Abate, D., Abay, S. M., Abbafati, C., Abdulkader, R. S., Abebe, Z., Aboyans, V., Abrar, M. M., Acharya, P., … Gakidou, E. (2018). Alcohol use and burden for 195 countries and territories, 1990–2016: A systematic analysis for the global burden of disease study 2016. The Lancet, 392(10152), 1015–1035. https://doi.org/10.1016/s0140-6736(18)31310-2 

[15]. American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders: DSM-5-TR. American Psychiatric Association Publishing. 

[16]. Ivanov, I., Newcorn, J., Morton, K., & Tricamo, M. (2011). Inhibitory control deficits in childhood: Definition, measurement, and clinical risk for Substance Use Disorders. Inhibitory Control and Drug Abuse Prevention, 125–144. https://doi.org/10.1007/978-1-4419-1268-8_7 

[17]. Moeller, F. G., Barratt, E. S., Dougherty, D. M., Schmitz, J. M., & Swann, A. C. (2001). Psychiatric aspects of impulsivity. American Journal of Psychiatry, 158(11), 1783–1793. https://doi.org/10.1176/appi.ajp.158.11.1783 

[18]. McClernon, F. J., & Kollins, S. H. (2008). ADHD and smoking. Annals of the New York Academy of Sciences, 1141(1), 131–147. https://doi.org/10.1196/annals.1441.016 

[19]. Shirley, M. C., & Sirocco, K. Y. (2014). Introduction to special section: ADHD, impulsivity, and alcohol abuse. Experimental and Clinical Psychopharmacology, 22(2), 97–99. https://doi.org/10.1037/a0036124 

[20]. Elkins, I. J., McGue, M., & Iacono, W. G. (2007). Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Archives of General Psychiatry, 64(10), 1145. https://doi.org/10.1001/archpsyc.64.10.1145 

[21]. Lee, S. S., Humphreys, K. L., Flory, K., Liu, R., & Glass, K. (2011). Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: A meta-analytic review. Clinical Psychology Review, 31(3), 328–341. https://doi.org/10.1016/j.cpr.2011.01.006 

[22]. Nutt, D. J., Lingford-Hughes, A., Erritzoe, D., & Stokes, P. R. (2015). The dopamine theory of addiction: 40 years of highs and lows. Nature Reviews Neuroscience, 16(5), 305–312. https://doi.org/10.1038/nrn3939 

[23]. Boileau, I., Assaad, J.-M., Pihl, R. O., Benkelfat, C., Leyton, M., Diksic, M., Tremblay, R. E., & Dagher, A. (2003). Alcohol promotes dopamine release in the human nucleus accumbens. Synapse, 49(4), 226–231. https://doi.org/10.1002/syn.10226 

[24]. Urban, N. B. L., Kegeles, L. S., Slifstein, M., Xu, X., Martinez, D., Sakr, E., Castillo, F., Moadel, T., O’Malley, S. S., Krystal, J. H., & Abi-Dargham, A. (2010). Sex differences in striatal dopamine release in young adults after oral alcohol challenge: A Positron emission tomography imaging study with [11C]Raclopride. Biological Psychiatry, 68(8), 689–696. https://doi.org/10.1016/j.biopsych.2010.06.005 

[25]. Biederman, J., Faraone, S. V. i, Spencer, T. J., Milberger, S., Mick, E., & Wilens, T. (1995). Psychoactive substance use disorders in adults with attention deficit hyperactivity disorder (ADHD): Effects of ADHD and psychiatric comorbidity. American Journal of Psychiatry, 152(11), 1652–1658. https://doi.org/10.1176/ajp.152.11.1652

[26]. Disney, E. R., Elkins, I. J., McGue, M., & Iacono, W. G. (1999). Effects of ADHD, conduct disorder, and gender on substance use and abuse in adolescence. American Journal of Psychiatry, 156(10), 1515–1521. https://doi.org/10.1176/ajp.156.10.1515 

[27]. Mochrie, K. D., Whited, M. C., Cellucci, T., Freeman, T., & Corson, A. T. (2018). ADHD, depression, and substance abuse risk among beginning college students. Journal of American College Health, 68(1), 6–10. https://doi.org/10.1080/07448481.2018.1515754 

[28]. Berridge, K. C., & Robinson, T. E. (2003). Parsing reward. Trends in Neurosciences, 26(9), 507–513. https://doi.org/10.1016/s0166-2236(03)00233-9 

[29]. Lee, S. S., & Humphreys, K. L. (2014). Interactive association of dopamine receptor (DRD4) genotype and ADHD on alcohol expectancies in children. Experimental and Clinical Psychopharmacology, 22(2), 100–109. https://doi.org/10.1037/a0035338

[30]. Clark, D. B., de Wit, H., & Iacono, W. G. (2014). ADHD, impulsivity and alcohol abuse: Methods, results, and implications. Experimental and Clinical Psychopharmacology, 22(2), 141–143. https://doi.org/10.1037/a0036140

[31]. Comings, D. E., Gonzalez, N., Wu, S., Gade, R., Muhleman, D., Saucier, G., Johnson, P., Verde, R., Rosenthal, R. J., Lesieur, H. R., Rugle, L. J., Miller, W. B., & MacMurray, J. P. (1999). Studies of the 48 BP repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. American Journal of Medical Genetics, 88(4), 358–368. https://doi.org/10.1002/(sici)1096-8628(19990820)88:4<358::aid-ajmg13>3.0.co;2-g

[32]. Grady, D. L., Chi, H.-C., Ding, Y.-C., Smith, M., Wang, E., Schuck, S., Flodman, P., Spence, M. A., Swanson, J. M., & Moyzis, R. K. (2003). High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder. Molecular Psychiatry, 8(5), 536–545. https://doi.org/10.1038/sj.mp.4001350 

[33]. Szobot, C. M., Roman, T., Hutz, M. H., Genro, J. P., Shih, M. C., Hoexter, M. Q., Júnior, N., Pechansky, F., Bressan, R. A., & Rohde, L. A. P. (2010). Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity. Synapse, 65(2), 154–159. https://doi.org/10.1002/syn.20829

[34]. Bauer, J., Werner, A., Kohl, W., Kugel, H., Shushakova, A., Pedersen, A., & Ohrmann, P. (2016). Hyperactivity and impulsivity in adult attention-deficit/hyperactivity disorder is related to glutamatergic dysfunction in the anterior cingulate cortex. The World Journal of Biological Psychiatry, 19(7), 538–546. https://doi.org/10.1080/15622975.2016.1262060

[35]. Huang, X., Wang, M., Zhang, Q., Chen, X., & Wu, J. (2019). The role of glutamate receptors in attention‐deficit/hyperactivity disorder: From physiology to disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 180(4), 272–286. https://doi.org/10.1002/ajmg.b.32726 

[36]. Luderer, M., Ramos Quiroga, J. A., Faraone, S. V., Zhang-James, Y., & Reif, A. (2021). Alcohol use disorders and ADHD. Neuroscience &amp; Biobehavioral Reviews, 128, 648–660. https://doi.org/10.1016/j.neubiorev.2021.07.010 

[37]. Tajbakhsh, A., Alimardani, M., Asghari, M., Abedini, S., Saghafi Khadem, S., Nesaei Bajestani, A., Alipoor, F., Alidoust, M., Savardashtaki, A., Hashemian, P., & Pasdar, A. (2021). Association of PICK1 and BDNF variations with increased risk of methamphetamine dependence among Iranian population: A case–control study. BMC Medical Genomics, 14(1). https://doi.org/10.1186/s12920-021-00873-7 

[38]. Kim, J. I., Kim, J.-W., Park, J.-E., Park, S., Hong, S.-B., Han, D. H., Cheong, J. H., Choi, J.-W., Lee, S., & Kim, B.-N. (2016). Association of the grin2b RS2284411 polymorphism with methylphenidate response in attention-deficit/hyperactivity disorder. Journal of Psychopharmacology, 31(8), 1070–1077. https://doi.org/10.1177/0269881116667707 

[39]. Sollis E, Mosaku A, Abid A, Buniello A, Cerezo M, Gil L, Groza T, Güneş O, Hall P, Hayhurst J, Ibrahim A, Ji Y, John S, Lewis E, MacArthur JAL, McMahon A, Osumi-Sutherland D, Panoutsopoulou K, Pendlington Z, Ramachandran S, Stefancsik R, Stewart J, Whetzel P, Wilson R, Hindorff L, Cunningham F, Lambert SA, Inouye M, Parkinson H, Harris LW. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2022 Nov 9:gkac1010. doi: 10.1093/nar/gkac1010. Epub ahead of print. PMID: 36350656.

[40]. Sullivan, P. F., Agrawal, A., Bulik, C. M., Andreassen, O. A., Børglum, A. D., Breen, G., Cichon, S., Edenberg, H. J., Faraone, S. V., Gelernter, J., Mathews, C. A., Nievergelt, C. M., Smoller, J. W., O’Donovan, M. C., & Psychiatric Genomics Consortium (2018). Psychiatric Genomics: An Update and an Agenda. The American journal of psychiatry, 175(1), 15–27. https://doi.org/10.1176/appi.ajp.2017.17030283

[41]. Sanchez-Roige, S., Palmer, A. A., Fontanillas, P., Elson, S. L., 23andMe Research Team, the Substance Use Disorder Working Group of the Psychiatric Genomics Consortium, Adams, M. J., Howard, D. M., Edenberg, H. J., Davies, G., Crist, R. C., Deary, I. J., McIntosh, A. M., & Clarke, T. K. (2019). Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts. The American journal of psychiatry, 176(2), 107–118. https://doi.org/10.1176/appi.ajp.2018.18040369

[42]. Johnson, E. C., Demontis, D., Thorgeirsson, T. E., Walters, R. K., Polimanti, R., Hatoum, A. S., Sanchez-Roige, S., Paul, S. E., Wendt, F. R., Clarke, T. K., Lai, D., Reginsson, G. W., Zhou, H., He, J., Baranger, D. A. A., Gudbjartsson, D. F., Wedow, R., Adkins, D. E., Adkins, A. E., Alexander, J., … Agrawal, A. (2020). A large-scale genome-wide association study meta-analysis of cannabis use disorder. The lancet. Psychiatry, 7(12), 1032–1045. https://doi.org/10.1016/S2215-0366(20)30339-4

[43]. Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., Maller, J., Sklar, P., de Bakker, P. I., Daly, M. J., & Sham, P. C. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics, 81(3), 559–575. https://doi.org/10.1086/519795

[44]. R Core Team (2023). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. <https://www.R-project.org/>.

[45]. Wickham H, François R, Henry L, Müller K, Vaughan D (2023). _dplyr: A Grammar of Data Manipulation_. R package version 1.1.2, <https://CRAN.R-project.org/package=dplyr>.

[46]. Stephen D. Turner (2018). qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots. Journal of Open Source Software, 3(25), 731 doi:10.21105/joss.00731

[47]. Sherry, S. T., Ward, M. H., Kholodov, M., Baker, J., Phan, L., Smigielski, E. M., & Sirotkin, K. (2001). dbSNP: the NCBI database of genetic variation. Nucleic acids research, 29(1), 308–311. https://doi.org/10.1093/nar/29.1.308

[48]. Wilson, J. J., & Levin, F. R. (2001). Attention deficit hyperactivity disorder (ADHD) and Substance Use Disorders. Current Psychiatry Reports, 3(6), 497–506. https://doi.org/10.1007/s11920-001-0044-8

[49]. Fan, Z., Qian, Y., Lu, Q., Wang, Y., Chang, S., & Yang, L. (2018). DLGAP1 and NMDA receptor-associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder. Brain and Behavior, 8(2). https://doi.org/10.1002/brb3.914

[50]. Clark, S. L., Chan, R. F., Zhao, M., Xie, L. Y., Copeland, W. E., Penninx, B. W., Aberg, K. A., & van den Oord, E. J. (2021). Dual methylation and hydroxymethylation study of alcohol use disorder. Addiction Biology, 27(2). https://doi.org/10.1111/adb.13114

[51]. Zhang, Z., Wei, S., Du, H., Su, Z., Wen, Y., Shang, Z., Song, X., Xu, Z., You, Y., & Yang, Z. (2019). ZFHX3 is required for the differentiation of late born D1-type medium spiny neurons. Experimental Neurology, 322, 113055. https://doi.org/10.1016/j.expneurol.2019.113055

[52]. Becchi, S., Buson, A., & Balleine, B. W. (2021). Inhibition of vascular adhesion protein 1 protects dopamine neurons from the effects of acute inflammation and restores habit learning in the striatum. Journal of Neuroinflammation, 18(1). https://doi.org/10.1186/s12974-021-02288-8

[53]. Zhang, M., Davis, J. E., Li, C., Gao, J., Huang, W., Lambert, N. A., Terry, A. V., & Wu, G. (2016). GGA3 interacts with a G protein-coupled receptor and modulates its cell surface export. Molecular and Cellular Biology, 36(7), 1152–1163. https://doi.org/10.1128/mcb.00009-16

[54]. Zhu, S., Zhao, C., Wu, Y., Yang, Q., Shao, A., Wang, T., Wu, J., Yin, Y., Li, Y., Hou, J., Zhang, X., Zhou, G., Gu, X., Wang, X., Bustelo, X. R., & Zhou, J. (2015). Identification of a VAV2-dependent mechanism for GDNF/ret control of Mesolimbic Dat Trafficking. Nature Neuroscience, 18(8), 1084–1093. https://doi.org/10.1038/nn.4060

[55]. Brosius, J. (2005). Waste not, want not – transcript excess in multicellular eukaryotes. Trends in Genetics, 21(5), 287–288. https://doi.org/10.1016/j.tig.2005.02.014

[56]. Badano, J. L., Ansley, S. J., Leitch, C. C., Lewis, R. A., Lupski, J. R., & Katsanis, N. (2003). Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. The American Journal of Human Genetics, 72(3), 650–658. https://doi.org/10.1086/368204

[57]. Pagano, M., Pepperkok, R., Verde, F., Ansorge, W., & Draetta, G. (1992). Cyclin A is required at two points in the human cell cycle. The EMBO Journal, 11(3), 961–971. https://doi.org/10.1002/j.1460-2075.1992.tb05135.x

[58]. Yoo, K.-S., Lee, K., Lee, Y.-S., Oh, W.-J., & Kim, H. K. (2020). Rho guanine nucleotide exchange factor 4 (ARHGEF4) deficiency enhances spatial and object recognition memory. Experimental Neurobiology, 29(5), 334–343. https://doi.org/10.5607/en20049

Cite this article

Gao,Y.;Sang,C.;Shen,G.;Xu,Y. (2024). Discovery of genes prominent in ADHD and SUDs: A meta-analysis and review. Theoretical and Natural Science,45,102-112.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

Disclaimer/Publisher's Note

The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of EWA Publishing and/or the editor(s). EWA Publishing and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

About volume

Volume title: Proceedings of the 2nd International Conference on Modern Medicine and Global Health

Conference website: https://www.icmmgh.org/
ISBN:978-1-83558-551-1(Print) / 978-1-83558-552-8(Online)
Conference date: 5 January 2024
Editor:Mohammed JK Bashir
Series: Theoretical and Natural Science
Volume number: Vol.45
ISSN:2753-8818(Print) / 2753-8826(Online)

© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Authors who publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open access policy for details).