Research Article
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The Association between GHRL and LEP Gene Polymorphisms and ADHD: Evidence from a Pediatric Cohort

Year 2025, Volume: 9 Issue: 2, 214 - 221, 31.08.2025

Abstract

Aim: Dopaminergic neurons and dopamine transporters show variations in Attention Deficit Hyperactivity Disorder (ADHD). Furthermore,
Ghrelin and leptin, hormones recognized for their neurotrophic effects, are significant in central nervous system regulation, influencing
neuronal survival and development.
Material and Methods: This study aimed to examine the potential relationship between Attention Deficit Hyperactivity Disorder (ADHD) and
polymorphisms in the GHRL (rs34911341) and LEP (rs7799039) genes. The research sample consisted of 29 children diagnosed with ADHD
and 24 age-matched healthy controls. Genotypic analysis was conducted using the polymerase chain reaction-restriction fragment length
polymorphism (PCR-RFLP) technique.
Results: A significant difference in genotype distribution for the GHRL gene rs34911341 polymorphism was observed between the ADHD
group and healthy controls (p = 0.036), whereas allele frequencies did not show a statistically significant difference (p = 0.207). In contrast,
analysis of the LEP gene rs7799039 polymorphism revealed no significant differences in either genotype (p = 0.579) or allele frequencies (p
= 0.558) between the two groups.
Conclusion: These findings suggest a potential role for the GHRL rs34911341 polymorphism in the development or presentation of ADHD.
Further research is required to elucidate the mechanisms underlying this association.

Ethical Statement

The study protocol was approved by Muğla Sıtkı Koçman University Faculty of Medicine Medical Ethics Committee with the decision of 28/07/2021 and 16/I. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Informed consent. Written informed consent was obtained from all patients prior to their participation in the study.

Supporting Institution

This paper was supported by ‘Scientific and Technological Research Council of Turkey (TUBITAK)

Project Number

1919B012101939

Thanks

I would like to thank our research team and all the individuals and institutions who contributed to our study for their support and contributions.

References

  • 1. Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J., Buitelaar, J. K., Ramos-Quiroga, J. A., Rohde, L. A., Sonuga- Barke, E. J. S., Tannock, R., & Franke, B. (2015). Attention- deficit/hyperactivity disorder. Nature Reviews Disease Primers, 1, Article 15020.
  • 2. Alvarez-Crespo, M., Skibicka, K. P., Farkas, I., Molnár, C. S., Egecioglu, E., Hrabovszky, E., ... & Dickson, S. L. (2012). The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence.
  • 3. Becer, E., & Ergoren, M. C. (2021). Dual effect of the GHRL gene variant in the molecular pathogenesis of obesity. Balkan Journal of Medical Genetics: BJMG, 24(1), 27.
  • 4. Gregoor, J. G., van der Weide, J., Mulder, H., Cohen, D., van Megen, H. J., Egberts, A. C., & Heerdink, E. R. (2009). Polymorphisms of the LEP-and LEPR gene and obesity in patients using antipsychotic medication. Journal of clinical psychopharmacology, 29(1), 21-25.
  • 5. araone S V., Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow- up studies. Psychological medicine. 2006;36(2):159-165. doi:10.1017/S003329170500471X
  • 6. Retz, W., Ginsberg, Y., Turner, D., Barra, S., Retz-Junginger, P., Larsson, H., & Asherson, P. (2021). Attention-Deficit/Hyperactivity Disorder (ADHD), antisociality and delinquent behavior over the lifespan. Neuroscience & Biobehavioral Reviews, 120, 236-248.
  • 7. Wu SY, Gau SSF. Correlates for academic performance and school functioning among youths with and without persistent attention-deficit/hyperactivity disorder. Research in Developmental Disabilities. 2013; 34(1):505-515. doi:10.1016/J. RIDD.2012.09.004
  • 8. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet. 1999;354(9196): 2132-2133. doi:10.1016/S0140-6736(99)04030-1
  • 9. Lange, M., Norton, W., Coolen, M., Chaminade, M., Merker, S., Proft, F., Schmitt, A., Vernier, P., Lesch, K.-P., & Bally-Cuif, L. (2012). The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Molecular Psychiatry, 17(10), 946–954.
  • 10. Cherkasova, M. V., Faridi, N., Casey, K. F., O’Driscoll, G. A., Hechtman, L., Joober, R., Baker, G. B., Palmer, J., Dagher, A., Leyton, M., & Benkelfat, C. (2014). Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD. Neuropsychopharmacology, 39(6), 1498– 1507.
  • 11. Swanson, J. M., Kinsbourne, M., Nigg, J., Lanphear, B., Stefanatos, G. A., Volkow, N., Taylor, E., Casey, B. J., Castellanos, F. X., & Wadhwa, P. D. (2007). Etiologic subtypes of attention- deficit/hyperactivity disorder: Brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychology Review, 17(1), 39–59.
  • 12. Shi, X., Guan, K., Peng, X., Xu, B., Zhou, X., Wang, S., Xu, S., Zheng, M., Huang, J., Wan, X., Guan, W., Su, K.-P., Ye, M., Gao, X., Yin, Z., & Li, X. (2021). Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models. Brain, Behavior, and Immunity, 94, 327–337.
  • 13. de Candia P, Matarese G. Leptin and ghrelin: Sewing metabolism onto neurodegeneration. Neuropharmacology. 2018;136:307- 316. doi:10.1016/J.NEUROPHARM.2017.12.025
  • 14. Schwartz MW, Baskin DG. Leptin and the brain: then and now. The Journal of Clinical Investigation. 2013;123(6):2344-2345. doi:10.1172/JCI69346
  • 15. Ahima RS, Bjorbæk C, Osei S, Flier JS. Regulation of Neuronal and Glial Proteins by Leptin: Implications for Brain Development. Endocrinology. 1999;140(6):2755-2762. doi:10.1210/ ENDO.140.6.6774
  • 16. Kohl M, Foulon C, Guelfi JD. [Hyperactivity and anorexia nervosa: behavioural and biological perspective]. L’encephale. 2004;30(5):492-499. doi:10.1016/S0013-7006(04)95463-2
  • 17. Zarouna S, Wozniak G, Papachristou AI. Mood disorders: A potential link between ghrelin and leptin on human body? World Journal of Experimental Medicine. 2015;5(2):103. doi:10.5493/ WJEM.V5.I2.103
  • 18. Lu XY, Kim CS, Fraser A, Zhang W. Leptin: A potential novel antidepressant. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(5):1593-1598. doi:10.1073/PNAS.0508901103/SUPPL_FILE/08901FIG8. JPG
  • 19. Turkmenoglu, M.F., Pektas Demir S, Demirtas Bilgic, A., Ozdemir C, Gokdogan Edgunlu T. GHRL Gene Polymorphisms in Early Onset Psoriasis: Molecular and In silico Analyses. Clinical Dermatology Open Access Journal. 2023;8(4):1-8. doi:10.23880/cdoaj-16000316
  • 20. Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR. Variants in the Ghrelin Gene Are Associated with Metabolic Syndrome in the Old Order Amish. The Journal of Clinical Endocrinology & Metabolism. 2005;90(12):6672-6677. doi:10.1210/JC.2005-0549
  • 21. Geisler, C. E., & Hayes, M. R. (2023). Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights. Physiology & behavior, 268, 114236.

GHRL ve LEP Gen Polimorfizmleri ile DEHB Arasındaki İlişki: Pediatrik Kohorttan Kanıtlar

Year 2025, Volume: 9 Issue: 2, 214 - 221, 31.08.2025

Abstract

Amaç: Dopaminerjik nöronlar ve dopamin taşıyıcıları Dikkat Eksikliği Hiperaktivite Bozukluğu'nda (DEHB) farklılıklar gösterir. Ayrıca,
nörotrofik etkileriyle tanınan hormonlar olan Ghrelin ve leptin, nöronal sağ kalımı ve gelişimi etkileyerek merkezi sinir sistemi düzenlemesinde
önemlidir.
Gereç ve Yöntemler: Bu çalışmanın amacı, DEHB ile GHRL (rs34911341) ve LEP (rs7799039) polimorfizmleri arasındaki ilişkiyi araştırmaktır.
Çalışmaya DEHB tanısı almış 29 çocuk ve 24 sağlıklı çocuk dahil edildi. Genotipleme, PCR-RFLP (polimeraz zincir reaksiyonu-restriksiyon
parça uzunluğu polimorfizmi) yöntemi aracılığıyla gerçekleştirildi.
Bulgular: GHRL geni rs34911341 polimorfizminin genotip sıklığı, DEHB ve sağlıklı kontrol grupları arasında önemli ölçüde farklılık gösterdi
(p=0,036), ancak alel sıklıkları önemli ölçüde farklılık göstermedi (p=0,207). LEP rs7799039 polimorfizmi için, iki grup arasında ne genotip
ne de alel frekansları farklı değildi (genotip frekansı için p=0,579; alel frekansı için p=0,558).
Sonuç: Bu bulgular, GHRL rs34911341 polimorfizminin DEHB'nin gelişiminde veya sunumunda potansiyel bir rolü olduğunu göstermektedir.
Bu ilişkinin altında yatan mekanizmaları açıklamak için daha fazla araştırma gerekmektedir.

Ethical Statement

Çalışma protokolü Muğla Sıtkı Koçman Üniversitesi Tıp Fakültesi Tıbbi Etik Kurulu'nun 28/07/2021 tarihli ve 16/I sayılı kararıyla onaylandı. Bu çalışmada kullanılan prosedürler Helsinki Bildirgesi ilkelerine uygundur. Bilgilendirilmiş onam. Çalışmaya katılmadan önce tüm hastalardan yazılı bilgilendirilmiş onam alındı.

Supporting Institution

Bu makale 'Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK)' tarafından desteklenmiştir.

Project Number

1919B012101939

Thanks

Araştırma ekibimize ve çalışmamıza katkı sağlayan tüm kişi ve kurumlara destek ve katkılarından dolayı teşekkür etmek isterim.

References

  • 1. Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J., Buitelaar, J. K., Ramos-Quiroga, J. A., Rohde, L. A., Sonuga- Barke, E. J. S., Tannock, R., & Franke, B. (2015). Attention- deficit/hyperactivity disorder. Nature Reviews Disease Primers, 1, Article 15020.
  • 2. Alvarez-Crespo, M., Skibicka, K. P., Farkas, I., Molnár, C. S., Egecioglu, E., Hrabovszky, E., ... & Dickson, S. L. (2012). The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence.
  • 3. Becer, E., & Ergoren, M. C. (2021). Dual effect of the GHRL gene variant in the molecular pathogenesis of obesity. Balkan Journal of Medical Genetics: BJMG, 24(1), 27.
  • 4. Gregoor, J. G., van der Weide, J., Mulder, H., Cohen, D., van Megen, H. J., Egberts, A. C., & Heerdink, E. R. (2009). Polymorphisms of the LEP-and LEPR gene and obesity in patients using antipsychotic medication. Journal of clinical psychopharmacology, 29(1), 21-25.
  • 5. araone S V., Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow- up studies. Psychological medicine. 2006;36(2):159-165. doi:10.1017/S003329170500471X
  • 6. Retz, W., Ginsberg, Y., Turner, D., Barra, S., Retz-Junginger, P., Larsson, H., & Asherson, P. (2021). Attention-Deficit/Hyperactivity Disorder (ADHD), antisociality and delinquent behavior over the lifespan. Neuroscience & Biobehavioral Reviews, 120, 236-248.
  • 7. Wu SY, Gau SSF. Correlates for academic performance and school functioning among youths with and without persistent attention-deficit/hyperactivity disorder. Research in Developmental Disabilities. 2013; 34(1):505-515. doi:10.1016/J. RIDD.2012.09.004
  • 8. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet. 1999;354(9196): 2132-2133. doi:10.1016/S0140-6736(99)04030-1
  • 9. Lange, M., Norton, W., Coolen, M., Chaminade, M., Merker, S., Proft, F., Schmitt, A., Vernier, P., Lesch, K.-P., & Bally-Cuif, L. (2012). The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Molecular Psychiatry, 17(10), 946–954.
  • 10. Cherkasova, M. V., Faridi, N., Casey, K. F., O’Driscoll, G. A., Hechtman, L., Joober, R., Baker, G. B., Palmer, J., Dagher, A., Leyton, M., & Benkelfat, C. (2014). Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD. Neuropsychopharmacology, 39(6), 1498– 1507.
  • 11. Swanson, J. M., Kinsbourne, M., Nigg, J., Lanphear, B., Stefanatos, G. A., Volkow, N., Taylor, E., Casey, B. J., Castellanos, F. X., & Wadhwa, P. D. (2007). Etiologic subtypes of attention- deficit/hyperactivity disorder: Brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychology Review, 17(1), 39–59.
  • 12. Shi, X., Guan, K., Peng, X., Xu, B., Zhou, X., Wang, S., Xu, S., Zheng, M., Huang, J., Wan, X., Guan, W., Su, K.-P., Ye, M., Gao, X., Yin, Z., & Li, X. (2021). Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models. Brain, Behavior, and Immunity, 94, 327–337.
  • 13. de Candia P, Matarese G. Leptin and ghrelin: Sewing metabolism onto neurodegeneration. Neuropharmacology. 2018;136:307- 316. doi:10.1016/J.NEUROPHARM.2017.12.025
  • 14. Schwartz MW, Baskin DG. Leptin and the brain: then and now. The Journal of Clinical Investigation. 2013;123(6):2344-2345. doi:10.1172/JCI69346
  • 15. Ahima RS, Bjorbæk C, Osei S, Flier JS. Regulation of Neuronal and Glial Proteins by Leptin: Implications for Brain Development. Endocrinology. 1999;140(6):2755-2762. doi:10.1210/ ENDO.140.6.6774
  • 16. Kohl M, Foulon C, Guelfi JD. [Hyperactivity and anorexia nervosa: behavioural and biological perspective]. L’encephale. 2004;30(5):492-499. doi:10.1016/S0013-7006(04)95463-2
  • 17. Zarouna S, Wozniak G, Papachristou AI. Mood disorders: A potential link between ghrelin and leptin on human body? World Journal of Experimental Medicine. 2015;5(2):103. doi:10.5493/ WJEM.V5.I2.103
  • 18. Lu XY, Kim CS, Fraser A, Zhang W. Leptin: A potential novel antidepressant. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(5):1593-1598. doi:10.1073/PNAS.0508901103/SUPPL_FILE/08901FIG8. JPG
  • 19. Turkmenoglu, M.F., Pektas Demir S, Demirtas Bilgic, A., Ozdemir C, Gokdogan Edgunlu T. GHRL Gene Polymorphisms in Early Onset Psoriasis: Molecular and In silico Analyses. Clinical Dermatology Open Access Journal. 2023;8(4):1-8. doi:10.23880/cdoaj-16000316
  • 20. Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR. Variants in the Ghrelin Gene Are Associated with Metabolic Syndrome in the Old Order Amish. The Journal of Clinical Endocrinology & Metabolism. 2005;90(12):6672-6677. doi:10.1210/JC.2005-0549
  • 21. Geisler, C. E., & Hayes, M. R. (2023). Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights. Physiology & behavior, 268, 114236.
There are 21 citations in total.

Details

Primary Language English
Subjects Paediatrics (Other)
Journal Section Research Article
Authors

Ali Atabek Kilic 0009-0003-1612-7591

Nilfer Şahin 0000-0001-7120-1561

Aysegul Demirtas Bilgic 0000-0002-6490-0169

Çilem Özdemir 0000-0002-3821-3621

Murat Cenik 0009-0002-6517-4522

Tuba Edgünlü 0000-0002-9300-9324

Project Number 1919B012101939
Publication Date August 31, 2025
Submission Date February 19, 2025
Acceptance Date April 23, 2025
Published in Issue Year 2025 Volume: 9 Issue: 2

Cite

Vancouver Kilic AA, Şahin N, Demirtas Bilgic A, Özdemir Ç, Cenik M, Edgünlü T. The Association between GHRL and LEP Gene Polymorphisms and ADHD: Evidence from a Pediatric Cohort. Med J West Black Sea. 2025;9(2):214-21.

Medical Journal of Western Black Sea is a scientific publication of Zonguldak Bulent Ecevit University Faculty of Medicine.

This is a refereed journal, which aims at achieving free knowledge to the national and international organizations and individuals related to medical sciences in publishedand electronic forms.

This journal is published three annually in April, August and December.
The publication language of the journal is Turkish and English.