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Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2019, Number 4

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Rev Invest Clin 2019; 71 (4)

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

Martínez-Magaña JJ, Genís-Mendoza AD, González-Covarrubias V, Jiménez-Guenchi J, Galindo-Chávez AG, Roche-Bergua A, Castañeda-González C, Lanzagorta N, Soberón X, Nicolini H

Language: English
References: 121
Page: 246-254
PDF size: 121.45 Kb.


ABSTRACT

Background: Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer’s type (DAT) or SCZ. Methods: We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results: We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion: As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.


REFERENCES

  1. Ngui EM, Khasakhala L, Ndetei D, Roberts LW. Mental disorders, health inequalities and ethics: a global perspective. Int Rev Psychiatry. 2010;22:235-44.

  2. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012; 380:2197-223.

  3. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3:171-8.

  4. Chaudhury PK, Deka K, Chetia D. Disability associated with mental disorders. Indian J Psychiatry. 2006;48:95-101.

  5. Ribe AR, Laursen TM, Charles M, Katon W, Fenger-Grøn M, Davydow D, et al. Long-term risk of dementia in persons with schizophrenia: a danish population-based cohort study. JAMA Psychiatry. 2015;72:1095-101.

  6. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for alzheimer’s disease. Nat Genet. 2013;45:1452-8.

  7. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421-7.

  8. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469-76.

  9. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11:446-50.

  10. Nelson MR, Wegmann D, Ehm MG, Kessner D, St Jean P, Verzilli C, et al. An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science. 2012;337:100-4.

  11. Mathieson I, Reich D. Differences in the rare variant spectrum among human populations. PLoS Genet. 2017;13:e1006581.

  12. Romero-Hidalgo S, Ochoa-Leyva A, Garcíarrubio A, Acuña- Alonzo V, Antúnez-Argüelles E, Balcazar-Quintero M, et al. Demographic history and biologically relevant genetic variation of native Mexicans inferred from whole-genome sequencing. Nat Commun. 2017;8:1005.

  13. Chagas MH, Pessoa RM, Almeida OP. Comparison of DSM-IV and DSM-5 dementia criteria among older people living in a community sample. Int J Geriatr Psychiatry. 2018;33:801-2.

  14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-98.

  15. Ostrosky-Solis F, Esther Gomez-Perez M, Matute E, Rosselli M, Ardila A, Pineda D, et al. Neuropsi attention and memory: a neuropsychological test battery in spanish with norms by age and educational level. Appl Neuropsychol. 2007;14:156-70.

  16. Pato MT, Sobell JL, Medeiros H, Abbott C, Sklar BM, Buckley PF, et al. The genomic psychiatry cohort: partners in discovery. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:306-12.

  17. Aprahamian I, Martinelli JE, Neri AL, Yassuda MS. The clock drawing test: a review of its accuracy in screening for dementia. Dement Neuropsychol. 2009;3:74-81.

  18. O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al. Staging dementia using clinical dementia rating scale sum of boxes scores: a Texas alzheimer’s research consortium study. Arch Neurol. 2008;65:1091-5.

  19. Zimmerman M, Chelminski I. A scale to screen for DSM-IV axis I disorders in psychiatric out-patients: performance of the psychiatric diagnostic screening questionnaire. Psychol Med. 2006; 36:1601-11.

  20. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr., Kawas CH, et al. The diagnosis of dementia due to alzheimer’s disease: recommendations from the national institute on agingalzheimer’s association workgroups on diagnostic guidelines for alzheimer’s disease. Alzheimers Dement. 2011;7:263-9.

  21. Nurnberger JI Jr., Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH genetics initiative. Arch Gen Psychiatry. 1994;51:849-59.

  22. Regier DA, Kuhl EA, Kupfer DJ. The DSM-5: classification and criteria changes. World Psychiatry. 2013;12:92-8.

  23. Lally J, Gaughran F, Timms P, Curran SR. Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics. Pharmgenomics Pers Med. 2016;9:117-29.

  24. Andreasen NC. Methods for assessing positive and negative symptoms. Mod Probl Pharmacopsychiatry. 1990;24:73-88.

  25. Genis-Mendoza AD, Martínez-Magaña JJ, Bojórquez C, Téllez- Martínez JA, Jiménez-Genchi J, Roche A, et al. Programa de detección del alelo APOE-E4 en adultos mayores mexicanos con deterioro cognitivo. Gac Med Mex. 2018;154:555-60.

  26. Giacopuzzi E, Gennarelli M, Minelli A, Gardella R, Valsecchi P, Traversa M, et al. Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways. PLoS One. 2017;12:e0182778.

  27. Guipponi M, Santoni FA, Setola V, Gehrig C, Rotharmel M, Cuenca M, et al. Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes. PLoS One. 2014; 9:e112745.

  28. Rafaniello C, Sessa M, Bernardi FF, Pozzi M, Cheli S, Cattaneo D, et al. The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions. Pharmacogenomics J. 2018;18:422-30.

  29. Cacabelos R. Pharmacogenomics of alzheimer’s and parkinson’s diseases. Neurosci Lett. 2018;18:S0304-3940(18):30624-4.

  30. Cacabelos R, Meyyazhagan A, Carril JC, Cacabelos P, Teijido Ó. Pharmacogenetics of vascular risk factors in alzheimer’s disease. J Pers Med. 2018;8:E3.

  31. Singh KK, De Rienzo G, Drane L, Mao Y, Flood Z, Madison J, et al. Common DISC1 polymorphisms disrupt wnt/GSK3β signaling and brain development. Neuron. 2011;72:545-58.

  32. Nguyen HT, Bryois J, Kim A, Dobbyn A, Huckins LM, Munoz- Manchado AB, et al. Integrated bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders. Genome Med. 2017;9:114.

  33. Butkiewicz M, Blue EE, Leung YY, Jian X, Marcora E, Renton AE, et al. Functional annotation of genomic variants in studies of lateonset alzheimer’s disease. Bioinformatics. 2018;34:2724-31.

  34. Zai CC, Tiwari AK, Zai GC, Maes MS, Kennedy JL. New findings in pharmacogenetics of schizophrenia. Curr Opin Psychiatry. 2018;31:200-12.

  35. Lord J, Lu AJ, Cruchaga C. Identification of rare variants in alzheimer’s disease. Front Genet. 2014;5:369.

  36. Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, et al. Whole-exome sequencing in 20,197 persons for rare variants in alzheimer’s disease. Ann Clin Transl Neurol. 2018;5:832-42.

  37. Gonzalez-Covarrubias V, Urena-Carrion J, Villegas-Torres B, Cossío-Aranda JE, Trevethan-Cravioto S, Izaguirre-Avila R, et al. Pharmacogenetic variation in over 100 genes in patients receiving acenocumarol. Front Pharmacol. 2017;8:863.

  38. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics. 2014;30:2114-20.

  39. Li H, Durbin R. Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics. 2009;25:1754-60.

  40. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921.

  41. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43:491-8.

  42. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From fastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43:11.10.1-33.

  43. Fromer M, Purcell SM. Using XHMM software to detect copy number variation in whole-exome sequencing data. Curr Protoc Hum Genet. 2014;81:7.23.1-21.

  44. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24-6.

  45. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016; 17:122.

  46. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980-5.

  47. Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE, et al. Pathogenic variant burden in the exAC database: an empirical approach to evaluating population data for clinical variant interpretation. Genome Med. 2017;9:13.

  48. 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68-74.

  49. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812-4.

  50. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using polyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:Unit7.20.

  51. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310-5.

  52. Rogers MF, Shihab HA, Mort M, Cooper DN, Gaunt TR, Campbell C, et al. FATHMM-XF: accurate prediction of pathogenic point mutations via extended features. Bioinformatics. 2018; 34:511-3.

  53. Hamosh A, Scott AF, Amberger J, Bocchini C, Valle D, McKusick VA, et al. Online mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res. 2002;30:52-5.

  54. Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE. Improving sequence variant descriptions in mutation databases and literature using the mutalyzer sequence variation nomenclature checker. Hum Mutat. 2008;29:6-13.

  55. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive pitt-hopkins-like mental retardation and determine the level of a common synaptic protein in drosophila. Am J Hum Genet. 2009;85:655-66.

  56. Harrison V, Connell L, Hayesmoore J, McParland J, Pike MG, Blair E, et al. Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am J Med Genet A. 2011;155A:2826-31.

  57. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795-803.

  58. Zhou Z, Gong Q, Epstein ML, January CT. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998;273:21061-6.

  59. Jiang YC, Wu HM, Cheng KH, Sun HS. Menstrual cycle-dependent febrile episode mediated by sequence-specific repression of poly(ADP-ribose) polymerase-1 on the transcription of the human serotonin receptor 1A gene. Hum Mutat. 2012;33:209-17.

  60. Fazzari P, Paternain AV, Valiente M, Pla R, Luján R, Lloyd K, et al. Control of cortical GABA circuitry development by nrg1 and erbB4 signalling. Nature. 2010;464:1376-80.

  61. Feng J, Schroer R, Yan J, Song W, Yang C, Bockholt A, et al. High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett. 2006;409:10-3.

  62. Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39:319-28.

  63. Yan J, Noltner K, Feng J, Li W, Schroer R, Skinner C, et al. Neurexin 1alpha structural variants associated with autism. Neurosci Lett. 2008;438:368-70.

  64. Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y, et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet. 2008;82:199-207.

  65. Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N, et al. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet. 2011;130:563-73.

  66. Apud JA, Zhang F, Decot H, Bigos KL, Weinberger DR. Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia. Am J Psychiatry. 2012;169:725-34.

  67. Hashimoto R, Ohi K, Yasuda Y, Fukumoto M, Yamamori H, Kamino K, et al. The KCNH2 gene is associated with neurocognition and the risk of schizophrenia. World J Biol Psychiatry. 2013;14:114-20.

  68. Huffaker SJ, Chen J, Nicodemus KK, Sambataro F, Yang F, Mattay V, et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med. 2009;15:509-18.

  69. Zuo L, Zhang XY, Wang F, Li CS, Lu L, Ye L, et al. Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence. Alcohol Clin Exp Res. 2013;37:730-9.

  70. Zuo L, Saba L, Lin X, Tan Y, Wang K, Krystal JH, et al. Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in caucasians. Am J Med Genet B Neuropsychiatr Genet. 2015;168:544-56.

  71. Gonzalez-Covarrubias V, Zhang J, Kalabus JL, Relling MV, Blanco JG. Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors. Drug Metab Dispos. 2009;37:400-7.

  72. Gonzalez-Covarrubias V, Kalabus JL, Blanco JG. Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). Pharm Res. 2008;25:1730-4.

  73. Hipfner DR, Deeley RG, Cole SP. Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta. 1999;1461: 359-76.

  74. Chang XB. A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. Cancer Metastasis Rev. 2007;26:15-37.

  75. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol. 2006;25:231-59.

  76. Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9:105-27.

  77. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003; 421:634-9.

  78. Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, et al. A cardiac arrhythmia syndrome caused by loss of ankyrin- B function. Proc Natl Acad Sci U S A. 2004;101:9137-42.

  79. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A. 1998;95:15718-23.

  80. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet. 2000;26:93-6.

  81. Dazzo E, Fanciulli M, Serioli E, Minervini G, Pulitano P, Binelli S, et al. Heterozygous reelin mutations cause autosomaldominant lateral temporal epilepsy. Am J Hum Genet. 2015; 96:992-1000.

  82. Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR, et al. Molecular cloning and functional expression of the human glycine transporter glyT2 and chromosomal localisation of the gene in the human genome. FEBS Lett. 1998;439:334-40.

  83. López-Corcuera B, Arribas-González E, Aragón C. Hyperekplexia- associated mutations in the neuronal glycine transporter 2. Neurochem Int. 2019;123:95-100.

  84. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994;7:195-200.

  85. Lemke JR, Hendrickx R, Geider K, Laube B, Schwake M, Harvey RJ, et al. GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Ann Neurol. 2014;75:147-54.

  86. Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021-6.

  87. O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43:585-9.

  88. Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017;54:460-70.

  89. Winham SJ, Cuellar-Barboza AB, McElroy SL, Oliveros A, Crow S, Colby CL, et al. Bipolar disorder with comorbid binge eating history: a genome-wide association study implicates APOB. J Affect Disord. 2014;165:151-8.

  90. Chen N, Bao Y, Xue Y, Sun Y, Hu D, Meng S, et al. Meta-analyses of RELN variants in neuropsychiatric disorders. Behav Brain Res. 2017;332:110-9.

  91. Fehér Á, Juhász A, Pákáski M, Kálmán J, Janka Z. Genetic analysis of the RELN gene: gender specific association with alzheimer’s disease. Psychiatry Res. 2015;230:716-8.

  92. Bufill E, Roura-Poch P, Sala-Matavera I, Antón S, Lleó A, Sánchez- Saudinós B, et al. Reelin signaling pathway genotypes and alzheimer disease in a spanish population. Alzheimer Dis Assoc Disord. 2015;29:169-72.

  93. Liu F, Arias-Vásquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, et al. A genomewide screen for late-onset alzheimer disease in a genetically isolated dutch population. Am J Hum Genet. 2007;81:17-31.

  94. Hennah W, Varilo T, Kestilä M, Paunio T, Arajärvi R, Haukka J, et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet. 2003;12:3151-9.

  95. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, et al. Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet. 2004;75:862-72.

  96. Coppedè F, Tannorella P, Pezzini I, Migheli F, Ricci G, Caldarazzo lenco E, et al. Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in lateonset alzheimer’s disease patients and healthy controls. Antioxid Redox Signal. 2012;17:195-204.

  97. Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, et al. Schizophrenia susceptibility pathway neuregulin 1-erbB4 suppresses src upregulation of NMDA receptors. Nat Med. 2011;17:470-8.

  98. Deng X, Sagata N, Takeuchi N, Tanaka M, Ninomiya H, Iwata N, et al. Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia. BMC Psychiatry. 2008;8:58.

  99. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet. 1996;58:17-20.

  100. Stevenson RE, Schwartz CE, Du YZ, Adams MJ Jr. Differences in methylenetetrahydrofolate reductase genotype frequencies, between whites and blacks. Am J Hum Genet. 1997;60:229-30.

  101. Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the hordaland homocysteine study. Arch Gen Psychiatry. 2003;60:618-26.

  102. Lewis SJ, Lawlor DA, Smith GD, Araya R, Timpson N, Day IN, et al. The thermolabile variant of MTHFR is associated with depression in the British women’s heart and health study and a meta-analysis. Mol Psychiatry. 2006;11:352-60.

  103. Takasaki Y, Koide T, Wang C, Kimura H, Xing J, Kushima I, et al. Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a japanese population. Sci Rep. 2016; 6:33311.

  104. Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med. 2006;12:824-8.

  105. Lutz SM, Frederiksen B, Begum F, McDonald MN, Cho MH, Hobbs BD, et al. Common and rare variants genetic association analysis of cigarettes per day among ever-smokers in chronic obstructive pulmonary disease cases and controls. Nicotine Tob Res. 2019;21:714-22.

  106. Del Monte-Nieto G, Ramialison M, Adam AA, Wu B, Aharonov A, D’Uva G, et al. Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature. 2018;557:439-45.

  107. Li B, Woo RS, Mei L, Malinow R. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron. 2007;54:583-97.

  108. Rodrigues-Amorim D, Rivera-Baltanás T, Bessa J, Sousa N, Vallejo- Curto MC, Rodríguez-Jamardo C, et al. The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: a meta-analysis. J Psychiatr Res. 2018;106:43-53.

  109. Vélez JI, Lopera F, Patel HR, Johar AS, Cai Y, Rivera D, et al. Mutations modifying sporadic alzheimer’s disease age of onset. Am J Med Genet B Neuropsychiatr Genet. 2016;171:1116-30.

  110. Asarnow RF, Forsyth JK. Genetics of childhood-onset schizophrenia. Child Adolesc Psychiatr Clin N Am. 2013;22:675-87.

  111. Chaumette B, Ferrafiat V, Ambalavanan A, Goldenberg A, Dionne- Laporte A, Spiegelman D, et al. Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia. Mol Psychiatry. 2018; volume 23.

  112. Stingl JC, Brockmöller J, Viviani R. Genetic variability of drugmetabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry. 2013;18: 273-87.

  113. Toselli F, Dodd PR, Gillam EM. Emerging roles for brain drugmetabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. Drug Metab Rev. 2016; 48:379-404.

  114. Westlind-Johnsson A, Hermann R, Huennemeyer A, Hauns B, Lahu G, Nassr N, et al. Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin Pharmacol Ther. 2006;79:339-49.

  115. Apellániz-Ruiz M, Inglada-Pérez L, Naranjo ME, Sánchez L, Mancikova V, Currás-Freixes M, et al. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the spanish population classifies CYP3A4 as a polymorphic enzyme. Pharmacogenomics J. 2015;15:288-92.

  116. Tóth K, Csukly G, Sirok D, Belic A, Kiss Á, Háfra E, et al. Potential role of patients’ CYP3A-status in clozapine pharmacokinetics. Int J Neuropsychopharmacol. 2017;20:529-37.

  117. Zhang XY, Wang HF, Tan MS, Wan Y, Kong LL, Zheng ZJ, et al. Association of DISC1 polymorphisms with late-onset alzheimer’s disease in northern han chinese. Mol Neurobiol. 2017;54: 2922-7.

  118. Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005;7:1167-78.

  119. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet. 1990;336:13-6.

  120. Zhou Z, Hu Z, Zhang L, Hu Z, Liu H, Liu Z, et al. Identification of RELN variation p.Thr3192Ser in a chinese family with schizophrenia. Sci Rep. 2016;6:24327.

  121. Krohn M, Bracke A, Avchalumov Y, Schumacher T, Hofrichter J, Paarmann K, et al. Accumulation of murine amyloid-β mimics early alzheimer’s disease. Brain. 2015;138:2370-82.




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