Abstract
The antisense non-coding RNA in the INK4 locus (ANRIL) is a long non-coding RNA (lncRNA) whose contribution in several human disorders has been verified. In the current projects, we genotyped two single nucleotide polymorphisms (SNPs) in this lncRNA (rs1333045 and rs1333048) in a population of Iranian patients with bipolar disorder (BP), major depressive disorder (MDD), and methamphetamine addiction. The rs1333045 was associated with methamphetamine addiction in recessive and multiplicative models (OR (95% CI) = 1.867 (1.211–2.877), adjusted p value = 8.75E−03 and OR (95% CI) = 1.415 (1.089–1.839), adjusted p value = 1.87E−02 respectively). The rs1333048 was associated with methamphetamine addiction in co-dominant model (A/A vs. C/C: OR (95% CI) = 0.195 (0.114–0.336), adjusted p value = 2.44E−09) and in other inheritance models. The rs1333045 was not associated with risk of BP I in any inheritance model. However, the rs1333048 was associated with BP I in co-dominant model (A/A vs. C/C: OR (95% CI) = 0.499 (0.286–0.870), adjusted p value = 2.53E−07) and in other inheritance models. In BP II cohort, we detected significant associations between both SNPs and risk of disorder in all inheritance models. In co-dominant model, these associations were detected just between homozygotes (T/T vs. C/C (rs1333045); A/A vs. C/C and (rs1333048)). The rs1333045 was associated with MDD in recessive model (OR (95% CI) = 2.221 (1.173–4.207), adjusted p value = 0.026). The rs1333048 was associated with MDDs in dominant, recessive, and multiplicative models. The selected SNPs were not in linkage disequilibrium (D′ statistic = 0.23, r2 = 0.05). Haplotype analyses have shown that T A haplotype block (rs1333045 and rs1333048 respectively) significantly decreases risk of addiction, BP I, BP II, and MDD. Besides, the C C haplotype decreases risk of addiction, BP II and MDD. Finally, the T C haplotype increases risk of BP I, BP II, and MDD. Based on the above-mentioned data, the selected ANRIL SNPs or other SNPs in linkage disequilibrium with them might confer risk of neuropsychiatric disorders. Taken together, ANRIL can be regarded as a risk locus for these conditions.
Similar content being viewed by others
References
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. BMC Med 17:133–137
Carmiol N, Peralta JM, Almasy L, Contreras J, Pacheco A, Escamilla MA, Knowles EE, Raventos H, Glahn DC (2014) Shared genetic factors influence risk for bipolar disorder and alcohol use disorders. Eur Psychiatry 29:282–287
Caviedes A, Lafourcade C, Soto C, Wyneken U (2017) BDNF/NF-kappaB signaling in the neurobiology of depression. Curr Pharm Des 23:3154–3163
Destoop M, Morrens M, Coppens V, Dom G (2019) Addiction, anhedonia, and comorbid mood disorder. A Narrative Review. Front Psychiatry 10:311
Emanuele E, Lista S, Ghidoni R, Binetti G, Cereda C, Benussi L, Maletta R, Bruni AC, POLITI P (2011) Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease. Neurobiol Aging 32:1231–1235
Horwitz T, Lam K, Chen Y, Xia Y, Liu C (2019) A decade in psychiatric GWAS research. Mol Psychiatry 24:378–389
Khorshidi HR, Taheri M, Noroozi R, Sarrafzadeh S, Sayad A, Ghafouri-Fard S (2017) ANRIL genetic variants in Iranian breast cancer patients. Cell Journal (Yakhteh) 19:72–78
Miklowitz DJ, Portnoff LC, Armstrong CC, Keenan-Miller D, Breen EC, Muscatell KA, Eisenberger NI, Irwin MR (2016) Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders. Psychiatry Res 241:315–322
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452
Olvera RL, Bearden CE, Velligan DI, Almasy L, Carless MA, Curran JE, Williamson DE, Duggirala R, Blangero J, Glahn DC (2011) Common genetic influences on depression, alcohol, and substance use disorders in Mexican-American families. Am J Med Genet B Neuropsychiatr Genet 156B:561–568
Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I (2007) Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res 67:3963–3969
Pasmant E, Sabbagh A, Vidaud M, Bieche I (2011) ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J 25:444–448
Quello SB, Brady KT, Sonne SC (2005) Mood disorders and substance use disorder: a complex comorbidity. Sci Pract Perspect 3:13–21
Rezazadeh M, Gharesouran J, Moradi M, Noroozi R, Omrani MD, Taheri M, Ghafouri-FARD S (2018) Association study of ANRIL genetic variants and multiple sclerosis. J Mol Neurosci 65:54–59
Scaini G, Fries GR, Valvassori SS, Zeni CP, Zunta-Soares G, Berk M, Soares JC, Quevedo J (2017) Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients. Transl Psychiatry 7:e1111
Taheri M, S G-F (2018) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Int J Cancer Manag 11:e67864
Uribe E, Wix R (2012) Neuronal migration, apoptosis and bipolar disorder. Rev Psiquiatr Salud Ment 5:127–133
Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934
Wen X, Han XR, Wang YJ, Wang S, Shen M, Zhang ZF, Fan SH, Shan Q, Wang L, Li MQ, Hu B, Sun CH, Wu DM, Lu J, Zheng YL (2018) Down-regulated long non-coding RNA ANRIL restores the learning and memory abilities and rescues hippocampal pyramidal neurons from apoptosis in streptozotocin-induced diabetic rats via the NF-kappaB signaling pathway. J Cell Biochem 119:5821–5833
Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T (2013) Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet 382:1575–1586
YE S, Dhillon S, Ke X, Collins AR, Day IN (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 29:E88–E88
Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H (2008) Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451:202–206
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Written informed consent was obtained from all enrolled individuals. The study protocol was approved by the ethics committees of Shahid Beheshti Universities of Medical Sciences.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Namvar, A., Kahaei, M.S., Fallah, H. et al. ANRIL Variants Are Associated with Risk of Neuropsychiatric Conditions. J Mol Neurosci 70, 212–218 (2020). https://doi.org/10.1007/s12031-019-01447-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01447-0