Abstract
Impaired sensorimotor circuits have been suggested in Attention-deficit/hyperactivity disorder (ADHD). NRXN1, highly expressed in cortex and cerebellum, was one of the candidate risk genes for ADHD, while its effects on sensorimotor circuits are unclear. In this content, we aimed to investigate the differential brain effects as functions of the cumulative genetic effects of NRXN1 variants in ADHD and healthy controls (HCs), identifying a potential pathway mapping from NRXN1, sensorimotor circuits, to ADHD. Magnetic resonance imaging, blood samples and clinical assessments were acquired from 53 male ADHD and 46 sex-matched HCs simultaneously. The effects of the cumulative genetic effects of NRXN1 variants valued by poly-variant risk score (PRS), on brain function was measured by resting-state functional connectivity (rs-FC) of cerebrocerebellar circuits. Mediation analyses were conducted to evaluate the association between NRXN1, functional abnormality, and ADHD diagnosis, as well as ADHD symptoms. The results were validated by bootstrapping and 10,000 times permutation tests. The rs-FC analyses demonstrated significant mediation models for ADHD diagnosis, and emphasized the involvement of cerebellum, middle cingulate gyrus and temporal gyrus, which are crucial parts of sensorimotor circuits. The current study suggested NRXN1 conferred risk for ADHD by regulating the function of sensorimotor circuits.
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Abbreviations
- MRI:
-
magnetic resonance imaging
- ROI:
-
region of interest
- PRS:
-
polygenic risk score
- rs-FC:
-
resting-state functional connectivity
References
An, L., Cao, Q. J., Sui, M. Q., Sun, L., Zou, Q. H., Zang, Y. F., et al., (2013). Local synchronization and amplitude of the fluctuation of spontaneous brain activity in attention-deficit/hyperactivity disorder: a resting-state fMRI study. Neuroscience Bulletin,29(5), 603–613. https://doi.org/10.1007/s12264-013-1353-8
Aoki, Y., Cortese, S., & Castellanos, F. X. (2018). Research Review: Diffusion tensor imaging studies of attention-deficit/hyperactivity disorder: meta-analyses and reflections on head motion. Journal of Child Psychology and Psychiatry and Allied Disciplines,59(3), 193–202. https://doi.org/10.1111/jcpp.12778
Ashburner, J. (2012). SPM: a history. NeuroImage,62(2), 791–800. https://doi.org/10.1016/j.neuroimage.2011.10.025
Bakhtiari, R., Mohammadi Sephavand, N., Nili Ahmadabadi, M., Araabi, N., & Esteky, H. (2012). Computational model of excitatory/inhibitory ratio imbalance role in attention deficit disorders. Journal of Computational Neuroscience,33(2), 389–404. https://doi.org/10.1007/s10827-012-0391-y
Barker, E. D., Ing, A., Biondo, F., Jia, T., Pingault, J. B., Rietz, D., et al., (2019). Do ADHD-impulsivity and BMI have shared polygenic and neural correlates? Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0444-y
Beaty, R. E., Benedek, M., Wilkins, R. W., Jauk, E., Fink, A., Silvia, P. J., et al., (2014). Creativity and the default network: A functional connectivity analysis of the creative brain at rest. Neuropsychologia,64, 92–98. https://doi.org/10.1016/j.neuropsychologia.2014.09.019
Berntson, G. G., Potolicchio, S. J., Jr., & Miller, N. E. (1973). Evidence for higher functions of the cerebellum: eating and grooming elicited by cerebellar stimulation in cats. Proceedings of the National Academy of Sciences of the United States of America,70(9), 2497–2499. https://doi.org/10.1073/pnas.70.9.2497
Cao, Q., Shu, N., An, L., Wang, P., Sun, L., Xia, M. R., et al., (2013). Probabilistic diffusion tractography and graph theory analysis reveal abnormal white matter structural connectivity networks in drug-naive boys with attention deficit/hyperactivity disorder. The Journal of Neuroscience,33(26), 10676–10687. https://doi.org/10.1523/jneurosci.4793-12.2013
Carmona, S., Hoekzema, E., Castellanos, F. X., García-García, D., Lage-Castellanos, A., Van Dijk, K. R., et al., (2015). Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder. Human Brain Mapping,36(7), 2544–2557. https://doi.org/10.1002/hbm.22790
Caviness, V. S., Jr., Meyer, J., Makris, N., & Kennedy, D. N. (1996). MRI-based topographic parcellation of human neocortex: an anatomically specified method with estimate of reliability. Journal of Cognitive Neuroscience,8(6), 566–587. https://doi.org/10.1162/jocn.1996.8.6.566
Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015). Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience,4, 7. https://doi.org/10.1186/s13742-015-0047-8
Chao-Gan, Y., & Yu-Feng, Z. (2010). DPARSF: A MATLAB Toolbox for “Pipeline” Data Analysis of Resting-State fMRI. Frontiers in Systems Neuroscience,4, 13. https://doi.org/10.3389/fnsys.2010.00013
Cortese, S., Kelly, C., Chabernaud, C., Proal, E., Di Martino, A., Milham, M. P., et al., (2012). Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. The American Journal of Psychiatry,169(10), 1038–1055. https://doi.org/10.1176/appi.ajp.2012.11101521
Cubillo, A., Smith, A. B., Barrett, N., Giampietro, V., Brammer, M. J., Simmons, A., et al., (2014). Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cereb Cortex,24(1), 174–185. https://doi.org/10.1093/cercor/bhs296
Curran, S., Ahn, J. W., Grayton, H., Collier, D. A., & Ogilvie, C. M. (2013). NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series - further understanding of the relevance of NRXN1 to neurodevelopmental disorders. J Mol Psychiatry,1(1), 4. https://doi.org/10.1186/2049-9256-1-4
Damoiseaux, J. S., & Greicius, M. D. (2009). Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity. Brain Structure & Function,213(6), 525–533. https://doi.org/10.1007/s00429-009-0208-6
Dean, C., Scholl, F. G., Choih, J., DeMaria, S., Berger, J., Isacoff, E., et al., (2003). Neurexin mediates the assembly of presynaptic terminals. Nature Neuroscience,6(7), 708–716. https://doi.org/10.1038/nn1074
Euesden, J., Lewis, C. M., & O’Reilly, P. F. (2015). PRSice: Polygenic Risk Score software. Bioinformatics, 31(9):1466–1468. https://doi.org/10.1093/bioinformatics/btu848
Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J., Buitelaar, J. K., Ramos-Quiroga, J. A., et al., (2015). Attention-deficit/hyperactivity disorder. Nature Reviews. Disease Primers,1, 15020. https://doi.org/10.1038/nrdp.2015.20
Filipek, P. A., Richelme, C., Kennedy, D. N., & Caviness, V. S., Jr. (1994). The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex,4(4), 344–360. https://doi.org/10.1093/cercor/4.4.344
Hart, H., Radua, J., Mataix-Cols, D., & Rubia, K. (2012). Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). Neuroscience and Biobehavioral Reviews,36(10), 2248–2256. https://doi.org/10.1016/j.neubiorev.2012.08.003
Hawi, Z., Cummins, T. D., Tong, J., Johnson, B., Lau, R., Samarrai, W., et al., (2015). The molecular genetic architecture of attention deficit hyperactivity disorder. Molecular Psychiatry,20(3), 289–297. https://doi.org/10.1038/mp.2014.183
Hayes, A. F. (2013). Introduction to mediation, moderation, and conditional process analysis: A regression-based approach. New York: The Guilford Press
Hermosillo, R. J. M., Mooney, M. A., Fezcko, E., Earl, E., Marr, M., Sturgeon, D., et al., (2019). Polygenic risk score-derived subcortical connectivity mediates attention-deficit/hyperactivity disorder diagnosis. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. https://doi.org/10.1016/j.bpsc.2019.11.014
Honey, C. J., Kotter, R., Breakspear, M., & Sporns, O. (2007). Network structure of cerebral cortex shapes functional connectivity on multiple time scales. Proceedings of the National Academy of Sciences of the United States of America,104(24), 10240–10245. https://doi.org/10.1073/pnas.0701519104
Hu, Z., Xiao, X., Zhang, Z., & Li, M. (2019). Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders. Molecular Psychiatry,24(10), 1400–1414. https://doi.org/10.1038/s41380-019-0438-9
Kattenstroth, G., Tantalaki, E., Sudhof, T. C., Gottmann, K., & Missler, M. (2004). Postsynaptic N-methyl-D-aspartate receptor function requires alpha-neurexins. Proceedings of the National Academy of Sciences of the United States of America,101(8), 2607–2612
Konrad, K., & Eickhoff, S. B. (2010). Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder. Human Brain Mapping,31(6), 904–916. https://doi.org/10.1002/hbm.21058
Kucyi, A., Hove, M. J., Biederman, J., Van Dijk, K. R., & Valera, E. M. (2015). Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder. Human Brain Mapping,36(9), 3373–3386. https://doi.org/10.1002/hbm.22850
Lee, S. J., Uemura, T., Yoshida, T., & Mishina, M. (2012). GluRdelta2 assembles four neurexins into trans-synaptic triad to trigger synapse formation. The Journal of Neuroscience,32(13), 4688–4701. https://doi.org/10.1523/jneurosci.5584-11.2012
Liston, C., Malter Cohen, M., Teslovich, T., Levenson, D., & Casey, B. J. (2011). Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point? Biological Psychiatry,69(12), 1168–1177. https://doi.org/10.1016/j.biopsych.2011.03.022
Liu, E. Y., Li, M., Wang, W., & Li, Y. (2013). MaCH-admix: genotype imputation for admixed populations. Genetic Epidemiology,37(1), 25–37. https://doi.org/10.1002/gepi.21690
Lu, Z., Wang, Y., Chen, F., Tong, H., Reddy, M. V., Luo, L., et al., (2014). Calsyntenin-3 molecular architecture and interaction with neurexin 1alpha. The Journal of Biological Chemistry,289(50), 34530–34542. https://doi.org/10.1074/jbc.M114.606806
Makransky, G., & Bilenberg, N. (2014). Psychometric properties of the parent and teacher ADHD Rating Scale (ADHD-RS): measurement invariance across gender, age, and informant. Assessment,21(6), 694–705. https://doi.org/10.1177/1073191114535242
Martin, J., Walters, R. K., Demontis, D., Mattheisen, M., Lee, S. H., Robinson, E., et al., (2018). A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder. Biological Psychiatry,83(12), 1044–1053. https://doi.org/10.1016/j.biopsych.2017.11.026
Montes, L. G., Ricardo-Garcell, J., De la Torre, L. B., Alcantara, H. P., Garcia, R. B., Acosta, D. A., et al., (2011). Cerebellar gray matter density in females with ADHD combined type: a cross-sectional voxel-based morphometry study. Journal of Attention Disorders,15(5), 368–381. https://doi.org/10.1177/1087054710366421
Neale, B. M., Medland, S., Ripke, S., Anney, R. J., Asherson, P., Buitelaar, J., et al., (2010). Case-control genome-wide association study of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry,49(9), 906–920. https://doi.org/10.1016/j.jaac.2010.06.007
Patterson, N., Price, A. L., & Reich, D. (2006). Population structure and eigenanalysis. PLoS Genetics,2(12), e190. https://doi.org/10.1371/journal.pgen.0020190
Pettem, K. L., Yokomaku, D., Luo, L., Linhoff, M. W., Prasad, T., Connor, S. A., et al., (2013). The specific alpha-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron,80(1), 113–128. https://doi.org/10.1016/j.neuron.2013.07.016
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics,38(8), 904–909. https://doi.org/10.1038/ng1847
Rademacher, J., Galaburda, A. M., Kennedy, D. N., Filipek, P. A., & Caviness, V. S., Jr. (1992). Human cerebral cortex: localization, parcellation, and morphometry with magnetic resonance imaging. Journal of Cognitive Neuroscience,4(4), 352–374. https://doi.org/10.1162/jocn.1992.4.4.352
Ray, S., Miller, M., Karalunas, S., Robertson, C., Grayson, D. S., Cary, R. P., et al., (2014). Structural and functional connectivity of the human brain in autism spectrum disorders and attention-deficit/hyperactivity disorder: A rich club-organization study. Human Brain Mapping,35(12), 6032–6048. https://doi.org/10.1002/hbm.22603
Reis, D. J., Doba, N., & Nathan, M. A. (1973). Predatory attack, grooming, and consummatory behaviors evoked by electrical stimulation of cat cerebellar nuclei. Science,182(4114), 845–847. https://doi.org/10.1126/science.182.4114.845
Reissner, C., Runkel, F., & Missler, M. (2013). Neurexins. Genome Biology,14(9), 213. https://doi.org/10.1186/gb-2013-14-9-213
Ribases, M., Bosch, R., Hervas, A., Ramos-Quiroga, J. A., Sanchez-Mora, C., Bielsa, A., et al., (2009). Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: association of BAIAP2 with attention-deficit/hyperactivity disorder. Biological Psychiatry,66(10), 926–934. https://doi.org/10.1016/j.biopsych.2009.06.024
Samea, F., Soluki, S., Nejati, V., Zarei, M., Cortese, S., Eickhoff, S. B., et al., (2019). Brain alterations in children/adolescents with ADHD revisited: A neuroimaging meta-analysis of 96 structural and functional studies. Neuroscience and Biobehavioral Reviews,100, 1–8. https://doi.org/10.1016/j.neubiorev.2019.02.011
Schaaf, C. P., Boone, P. M., Sampath, S., Williams, C., Bader, P. I., Mueller, J. M., et al., (2012). Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. European Journal of Human Genetics,20(12), 1240–1247. https://doi.org/10.1038/ejhg.2012.95
Shang, C. Y., Lin, H. Y., & Gau, S. S. (2019). The norepinephrine transporter gene modulates intrinsic brain activity, visual memory, and visual attention in children with attention-deficit/hyperactivity disorder. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0545-7
Shang, C. Y., Lin, H. Y., & Gau, S. S. (2020). Effects of the dopamine transporter gene on striatal functional connectivity in youths with attention-deficit/hyperactivity disorder. Psychological Medicine, 1–11. https://doi.org/10.1017/s0033291719003830
Shaw, P., Gilliam, M., Liverpool, M., Weddle, C., Malek, M., Sharp, W., et al., (2011). Cortical development in typically developing children with symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit hyperactivity disorder. The American Journal of Psychiatry,168(2), 143–151. https://doi.org/10.1176/appi.ajp.2010.10030385
Shaw, P., Ishii-Takahashi, A., Park, M. T., Devenyi, G. A., Zibman, C., Kasparek, S., et al., (2018). A multicohort, longitudinal study of cerebellar development in attention deficit hyperactivity disorder. Journal of Child Psychology and Psychiatry and Allied Disciplines,59(10), 1114–1123. https://doi.org/10.1111/jcpp.12920
Shaw, P., Lerch, J., Greenstein, D., Sharp, W., Clasen, L., Evans, A., et al., (2006). Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Archives of General Psychiatry,63(5), 540–549. https://doi.org/10.1001/archpsyc.63.5.540
Shaw, P., Malek, M., Watson, B., Greenstein, D., de Rossi, P., & Sharp, W. (2013). Trajectories of cerebral cortical development in childhood and adolescence and adult attention-deficit/hyperactivity disorder. Biological Psychiatry,74(8), 599–606. https://doi.org/10.1016/j.biopsych.2013.04.007
Stoodley, C. J. (2014). Distinct regions of the cerebellum show gray matter decreases in autism, ADHD, and developmental dyslexia. Frontiers in Systems Neuroscience,8, 92. https://doi.org/10.3389/fnsys.2014.00092
Sudhof, T. C. (2017). Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell,171(4), 745–769. https://doi.org/10.1016/j.cell.2017.10.024
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), e994-1001. https://doi.org/10.1542/peds.2014-3482
Ushkaryov, Y. A., Petrenko, A. G., Geppert, M., & Sudhof, T. C. (1992). Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science,257(5066), 50–56
Valera, E. M., Faraone, S. V., Murray, K. E., & Seidman, L. J. (2007). Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biological Psychiatry,61(12), 1361–1369. https://doi.org/10.1016/j.biopsych.2006.06.011
Voineskos, A. N., Lett, T. A., Lerch, J. P., Tiwari, A. K., Ameis, S. H., Rajji, T. K., et al., (2011). Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders. PLoS One1,6(6), e20982. https://doi.org/10.1371/journal.pone.0020982
Wolf, R. C., Plichta, M. M., Sambataro, F., Fallgatter, A. J., Jacob, C., Lesch, K. P., et al., (2009). Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention-deficit/hyperactivity disorder. Human Brain Mapping,30(7), 2252–2266. https://doi.org/10.1002/hbm.20665
Wolosin, S. M., Richardson, M. E., Hennessey, J. G., Denckla, M. B., & Mostofsky, S. H. (2009). Abnormal cerebral cortex structure in children with ADHD. Human Brain Mapping,30(1), 175–184. https://doi.org/10.1002/hbm.20496
Yang, L., Neale, B. M., Liu, L., Lee, S. H., Wray, N. R., Ji, N., et al., (2013). Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics,162b(5), 419–430. https://doi.org/10.1002/ajmg.b.32169
Zanchetti, A., & Zoccolini, A. (1954). Autonomic hypothalamic outbursts elicited by cerebellar stimulation. Journal of Neurophysiology,17(5), 475–483. https://doi.org/10.1152/jn.1954.17.5.475
Zhang-James, Y., Helminen, E. C., Liu, J., Franke, B., Hoogman, M., & Faraone, S. V. (2021). Evidence for similar structural brain anomalies in youth and adult attention-deficit/hyperactivity disorder: a machine learning analysis. Translational Psychiatry,11(1), 82. https://doi.org/10.1038/s41398-021-01201-4
Zimmermann, J., Deris, N., Montag, C., Reuter, M., Felten, A., Becker, B., et al., (2018). A common polymorphism on the oxytocin receptor gene (rs2268498) and resting-state functional connectivity of amygdala subregions - A genetic imaging study. NeuroImage,179, 1–10. https://doi.org/10.1016/j.neuroimage.2018.06.014
Acknowledgements
We thank all the patients who participated in this study, as well as the colleagues contributed in the data collection. Yuanxin Zhong: Conceptualization, Methodology, Data curation, Software, Writing- Original draft preparation, Writing- Reviewing and Editing. Li An: Data Collection. Yufeng Wang: Supervision. Li Yang: Supervision, Writing- Reviewing and Editing. Qingjiu Cao: Supervision, Validation, Writing- Reviewing and Editing.
Funding
This work was supported by grants from National Key R&D Program of China (2016YFC1306103), National Natural Science Foundation of China (grant numbers: 81671358, 81873804, 81873803, 81761128035), the Major State Basic Research Development Program of China (973Program, 2014CB846100). Beijing Municipal Science and Technology Commission (Z181100001518005).
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Zhong, Y., An, L., Wang, Y. et al. Functional abnormality in the sensorimotor system attributed to NRXN1 variants in boys with attention deficit hyperactivity disorder. Brain Imaging and Behavior 16, 967–976 (2022). https://doi.org/10.1007/s11682-021-00579-5
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DOI: https://doi.org/10.1007/s11682-021-00579-5