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Genes and SNPs Associated with Schizophrenia

2013, Jul 18 Neural markers of errors as endophenotypes in neuropsychiatric disorders, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School  “Converging lines of evidence support a role for DA in error processing.

2012, May 15 Researchers identify key genes and prototype predictive test for schizophrenia, Indiana University School of Medicine, May 15, 2012  An Indiana University-led research team, along with a group of national and international collaborators, has identified and prioritized a comprehensive group of genes most associated with schizophrenia that together can generate a score indicating whether an individual is at higher or lower risk of developing the disease…“At its core, schizophrenia is a disease of decreased cellular connectivity in the brain, precipitated by environmental stress during brain development, among those with genetic vulnerability,” said principal investigator Alexander B. Niculescu III, M.D., Ph.D., associate professor of psychiatry and medical neuroscience at the IU School of Medicine and director of the Laboratory of Neurophenomics at the Institute of Psychiatric Research at the IU School of Medicine…He stressed that a score indicating a higher risk of schizophrenia “doesn’t determine your destiny. It just means that your neuronal connectivity is different, which could make you more creative, or more prone to illness.”…The authors noted that the results were stronger when analyses were performed using gene-level data, rather than analyses based on individual mutations — called single nucleotide polymorphisms, or SNPs — in those genes. Multiple different SNPs can spark a particular gene’s role in the development of schizophrenia, so evidence for the genes, and the biological mechanisms in which they play a role, was much stronger from study to study than was the evidence for individual SNPs.  Additional authors of the paper are Mikias Ayalew, Helen Le-Niculescu, Daniel Levey, Nitika Jain, Bharathi Eddula-Changala, Sagar Patel, Evan Winiger, Alan Breier, Anantha Shekhar, John Nurnberger, and Daniel  Koller from IU; Aiden Corvin from Trinity College; Mark Geyer and Ming Tsuang from UC San Diego; Daniel Salomon and Nicholas Schork from The Scripps Research Institute; Richard Amdur and Ayman Fanous from Washington DC VA Medical Center; and Michael O’ Donovan from Cardiff University.   Support for the research was provided by a National Institutes of Health Director’s New Innovator Award (1DP2OD007363) and a Veterans Administration Merit Award (1I01CX000139-01). http://communications.medicine.iu.edu/newsroom/stories/2012/researchers-identify-key-genes-and-prototype-predictive-test-for/

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Genes Associated with Schizophrenia: Ranked by Harvard Genotator  

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http://genotator.hms.harvard.edu/geno/

  • 74.1  COMT – catechol-O-methyltransferase, one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine.Patients with genotype Val/ Val of polymorphism Val 158MetCOMT showed major cognitive deficits.  Studies found a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. Lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures. Allelic variation at the COMT Val (158)Met locus may influence signal discrimination capacity in schizophrenia. Val loading, probably due to decreased prefrontal dopamine availability, is associated with greater cognitive flexibility, which in turn may influence other cognitive measures that have been associated with COMT to date. During cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Male subjects with the COMT Met158Met-genotype also showed elevated PPI – Prepulse inhibition (PPI) of the acoustic startle response (ASR), an operational measure of sensorimotor gating. So, the influence of the COMT Val158Met genotype on PPI appears to be sex-specific. (Sex differences and hormonal influences in human sensorimotor gating: implications for schizophrenia)  findings suggest that individuals with the met allele are less sensitive to the cognitive enhancing effects of stimulant drugs.  22a11DS is associated with  larger prefrontal cortical thickness in adolescents. 10% reduction in connective fibers in the left frontal temporo regions and within and between limbic structures for those with 22q11.2 deletion syndrome.
  • 64.9  DRD2 – dopamine receptor D2, This G protein-coupled receptor inhibits adenylyl cyclase activity (adenylyl cyclase is an enzyme with key regulatory roles in nearly all cells. All classes of AC catalyze the conversion of ATP to 3′,5′-cyclic AMP (cAMP) and pyrophosphate.) A allele of rs1079727, G allele of rs2283265, A allele of rs1124492 and the risk haplotype (A-C-G) of block 3 were associated with more severe negative symptoms. With regard to neuropsychological performance, the risk haplotype (G-A-C-T) of block 4 was associated with poorer performance in the sustained attention task
  • 53.6  BDNF – brain-derived neurotrophic factor. Youth carrying at least one copy of the Met allele were more sensitive to the duration of deprivation in orphanages, yielding an interaction that followed a differential susceptibility pattern.
  • 40.9  DRD3 – dopamine receptor D3
  • 31.3  NRG1 – neuregulin 1
  • 31.0  HTR2A – 5-hydroxytryptamine (serotonin) receptor 2A
  • 25.1  DISC1 – disrupted in schizphrenia 1
  • 24.6  DTNBP1 – dystrobrevin binding protein 1
  • 24.5  SLC6A4 – solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (5-HTT, 5-HTTLPR, 5HTT, HTT, OCD1, SERT, hSERT, 5HT transporter)
  • 23.5  MTHFR – 5,10-methylenetetrahydrofolate reductase (NADPH) Females with the 677TT genotype had the lowest methylation (56%) compared with the other groups (75%). (MTHFR 677C>T, rs1801133) is associated with increased perseverative errors among patients. (Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments.) Biochemical, physiological and clinical effects of lmethylfolate in schizophrenia: a randomized controlled trial, Nature.com, Molecular Psychiatry advance online publication 14 March 2017. :
    Patients receiving l-methyl folate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity, and increased cortical thickness.
  • 21.8 ANKK1 – ankyrin repeat and kinase domain containing 1
  • 21.3  ACSL6 – acyl-CoA synthetase long-chain family member 6
  • 20.1  DAOA – D-amino acid oxidase activator
  • 20.0  DRD4  – dopamine receptor D4
  • 19.3  SIRT5 – sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae)
  • 15.8  CYP2D6 – cytochrome P450, family 2, subfamily D, polypeptide 6
  • 15.3  HTR2C – 5-hydroxytryptamine (serotonin) receptor 2C
  • 13.6  TPH1 – tryptophan hydroxylase 1
  • 12.7 AKT1 – v-akt murine thymoma viral oncogene homolog1
  • 12.1  SLC6A3 – solute carrier family 6 (neurotransmitter transporter, dopamine), member 3, The dopamine transporter (SLC6A3; DAT1; DAT) is a direct target of stimulant drugs.  polymorphisms in SLC6A3 play an important role in responses to stimulant.  individuals may require more methylphenidate due to increased dopamine transporter density within the brain.
  • 10.9 RGS4 – regulator of G-protein signaling 4
  • 10.5 NOTCH4 – Notch homolog 4 (drosophilia)
  • 10.1 APOE – apolipoprotein E

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