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
Ali Atabek Kilic
,
Nilfer Şahin
,
Aysegul Demirtas Bilgic
,
Çilem Özdemir
,
Murat Cenik
,
Tuba Edgünlü
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
Ali Atabek Kilic
,
Nilfer Şahin
,
Aysegul Demirtas Bilgic
,
Çilem Özdemir
,
Murat Cenik
,
Tuba Edgünlü
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.