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The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

  • A. Hargreaves (a1), R. Anney (a1), C. O'Dushlaine (a1), K. K. Nicodemus (a1), Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), Wellcome Trust Case Control Consortium 2, M. Gill (a1), A. Corvin (a1), D. Morris (a1) and Gary Donohoe (a1) (a2)...
Abstract
Background

Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients.

Method

In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability.

Results

Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1–3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis.

Conclusions

These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.

Copyright
Corresponding author
* Address for correspondence: Professor G. Donohoe, National University of Ireland, Galway, Republic of Ireland. (Email: donoghug@tcd.ie)
References
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BellenguezC, BevanS, GschwendtnerA, SpencerCC, BurgessAI, PirinenM, JacksonCA, TraylorM, StrangeA, SuZ, BandG, SymePD, MalikR, PeraJ, NorrvingB, LemmensR, FreemanC, SchanzR, JamesT, PooleD, MurphyL, SegalH, CortelliniL, ChengYC, WooD, NallsMA, Muller-MyhsokB, MeisingerC, SeedorfU, Ross-AdamsH, BoonenS, Wloch-KopecD, ValantV, SlarkJ, FurieK, DelavaranH, LangfordC, DeloukasP, EdkinsS, HuntS, GrayE, DronovS, PeltonenL, GretarsdottirS, ThorleifssonG, ThorsteinsdottirU, StefanssonK, BoncoraglioGB, ParatiEA, AttiaJ, HollidayE, LeviC, FranzosiMG, GoelA, HelgadottirA, BlackwellJM, BramonE, BrownMA, CasasJP, CorvinA, DuncansonA, JankowskiJ, MathewCG, PalmerCN, PlominR, RautanenA, SawcerSJ, TrembathRC, ViswanathanAC, WoodNW, WorrallBB, KittnerSJ, MitchellBD, KisselaB, MeschiaJF, ThijsV, LindgrenA, MacleodMJ, SlowikA, WaltersM, RosandJ, SharmaP, FarrallM, SudlowCL, RothwellPM, DichgansM, DonnellyP, MarkusHS (2012). Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics 44, 328333.
CambonK, HansenSM, VeneroC, HerreroAI, SkiboG, BerezinV, BockE, SandiC (2004). A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. Journal of Neuroscience 24, 41974204.
CornblattBA, RischNJ, FarisG, FriedmanD, Erlenmeyer-KimlingL (1988). The Continuous Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Research 26, 223238.
CummingsE, DonohoeG, HargreavesA, MooreS, FaheyC, DinanTG, McDonaldC, O'CallaghanE, O'NeillFA, WaddingtonJL, MurphyKC, MorrisDW, GillM, CorvinA (2013). Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137. Neuroscience Letters 532, 3338.
DeanC, SchollFG, ChoihJ, DeMariaS, BergerJ, IsacoffE, ScheiffeleP (2003). Neurexin mediates the assembly of presynaptic terminals. Nature Neuroscience 6, 708716.
FirstM, SpitzerR, GibbonM, WilliamsJ (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York.
FowlerT, ZammitS, OwenMJ, RasmussenF (2012). A population-based study of shared genetic variation between premorbid IQ and psychosis among male twin pairs and sibling pairs from Sweden. Archives of General Psychiatry 69, 460466.
FriedmanJI, VrijenhoekT, MarkxS, JanssenIM, van der VlietWA, FaasBH, KnoersNV, CahnW, KahnRS, EdelmannL, DavisKL, SilvermanJM, BrunnerHG, van KesselAG, WijmengaC, OphoffRA, VeltmanJA (2008). CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular Psychiatry 13, 261266.
GreenwoodTA, LazzeroniLC, MurraySS, CadenheadKS, CalkinsME, DobieDJ, GreenMF, GurRE, GurRC, HardimanG, KelsoeJR, LeonardS, LightGA, NuechterleinKH, OlincyA, RadantAD, SchorkNJ, SeidmanLJ, SieverLJ, SilvermanJM, StoneWS, SwerdlowNR, TsuangDW, TsuangMT, TuretskyBI, FreedmanR, BraffDL (2011). Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. American Journal of Psychiatry 168, 930946.
International Schizophrenia Consortium; PurcellSM, WrayNR, StoneJL, VisscherPM, O'DonovanMC, SullivanPF, SklarP (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752.
Irish Schizophrenia Genomics Consortium (2012). Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biological Psychiatry 72, 620628.
JiaP, WangL, FanousAH, ChenX, KendlerKS, ZhaoZ (2012). A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia. Journal of Medical Genetics 49, 96103.
KirovG, PocklingtonAJ, HolmansP, IvanovD, IkedaM, RuderferD, MoranJ, ChambertK, TonchevaD, GeorgievaL, GrozevaD, FjodorovaM, WollertonR, ReesE, NikolovI, van de LagemaatLN, BayesA, FernandezE, OlasonPI, BottcherY, KomiyamaNH, CollinsMO, ChoudharyJ, StefanssonK, StefanssonH, GrantSG, PurcellS, SklarP, O'DonovanMC, OwenMJ (2012). De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Molecular Psychiatry 17, 142153.
KosM, van den BrinkD, SnijdersTM, RijpkemaM, FrankeB, FernandezG, HagoortP (2012). CNTNAP2 and language processing in healthy individuals as measured with ERPs. PLOS ONE 7, e46995.
LipsES, CornelisseLN, ToonenRF, MinJL, HultmanCM, HolmansPA, O'DonovanMC, PurcellSM, SmitAB, VerhageM, SullivanPF, VisscherPM, PosthumaD (2012). Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Molecular Psychiatry 17, 9961006.
McGuffinP, FarmerA, HarveyI (1991). A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764770.
McIntoshAM, GowA, LucianoM, DaviesG, LiewaldDC, HarrisSE, CorleyJ, HallJ, StarrJM, PorteousDJ, TenesaA, VisscherPM, DearyIJ (2013). Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biological Psychiatry 73, 938943.
O'DushlaineC, KennyE, HeronE, DonohoeG, GillM, MorrisD, CorvinA (2011). Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Molecular Psychiatry 16, 286292.
RipkeS, SandersAR, KendlerKS, LevinsonDF, SklarP, HolmansPA, LinDY, DuanJ, OphoffRA, AndreassenOA, ScolnickE, CichonS, St ClairD, CorvinA, GurlingH, WergeT, RujescuD, BlackwoodDH, PatoCN, MalhotraAK, PurcellS, DudbridgeF, NealeBM, RossinL, VisscherPM, PosthumaD, RuderferDM, FanousA, StefanssonH, SteinbergS, MowryBJ, GolimbetV, De HertM, JonssonEG, BitterI, PietilainenOP, CollierDA, TosatoS, AgartzI, AlbusM, AlexanderM, AmdurRL, AminF, BassN, BergenSE, BlackDW, BorglumAD, BrownMA, BruggemanR, BuccolaNG, ByerleyWF, CahnW, CantorRM, CarrVJ, CattsSV, ChoudhuryK, CloningerCR, CormicanP, CraddockN, DanoyPA, DattaS, de HaanL, DemontisD, DikeosD, DjurovicS, DonnellyP, DonohoeG, DuongL, DwyerS, Fink-JensenA, FreedmanR, FreimerNB, FriedlM, GeorgievaL, GieglingI, GillM, GlenthojB, GodardS, HamshereM, HansenM, HansenT, HartmannAM, HenskensFA, HougaardDM, HultmanCM, IngasonA, JablenskyAV, JakobsenKD, JayM, JurgensG, KahnRS, KellerMC, KenisG, KennyE, KimY, KirovGK, KonnerthH, KonteB, KrabbendamL, KrasuckiR, et al. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics 43, 969976.
RobbinsTW, JamesM, OwenAM, SahakianBJ, McInnesL, RabbittP (1994). Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5, 266281.
RobertsonI (1994). Sustained Attention to Response Task (SART). Trinity College Dublin: Dublin.
RujescuD, IngasonA, CichonS, PietilainenOP, BarnesMR, ToulopoulouT, PicchioniM, VassosE, EttingerU, BramonE, MurrayR, RuggeriM, TosatoS, BonettoC, SteinbergS, SigurdssonE, SigmundssonT, PeturssonH, GylfasonA, OlasonPI, HardarssonG, JonsdottirGA, GustafssonO, FossdalR, GieglingI, MollerHJ, HartmannAM, HoffmannP, CrombieC, FraserG, WalkerN, LonnqvistJ, SuvisaariJ, Tuulio-HenrikssonA, DjurovicS, MelleI, AndreassenOA, HansenT, WergeT, KiemeneyLA, FrankeB, VeltmanJ, Buizer-VoskampJE, SabattiC, OphoffRA, RietschelM, NothenMM, StefanssonK, PeltonenL, St ClairD, StefanssonH, CollierDA (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics 18, 988996.
SeshadriS, DeStefanoAL, AuR, MassaroJM, BeiserAS, Kelly-HayesM, KaseCS, D'AgostinoRBSr, DecarliC, AtwoodLD, WolfPA (2007). Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Medical Genetics 8 (Suppl. 1), S15.
ShatzCJ (2009). MHC class I: an unexpected role in neuronal plasticity. Neuron 64, 4045.
SoronenP, OllilaHM, AntilaM, SilanderK, PaloOM, KieseppaT, LonnqvistJ, PeltonenL, Tuulio-HenrikssonA, PartonenT, PaunioT (2010). Replication of GWAS of bipolar disorder: association of SNPs near CDH7 with bipolar disorder and visual processing. MolecularPsychiatry 15, 46.
SPSS (2008). SPSS 16.0 Command Syntax Reference. SPSS Inc.: Chicago.
SunC, ChengMC, QinR, LiaoDL, ChenTT, KoongFJ, ChenG, ChenCH (2011). Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Human Molecular Genetics 20, 30423051.
ToulopoulouT, PicchioniM, RijsdijkF, Hua-HallM, EttingerU, ShamP, MurrayR (2007). Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Archives of General Psychiatry 64, 13481355.
VoineskosAN, LettTA, LerchJP, TiwariAK, AmeisSH, RajjiTK, MullerDJ, MulsantBH, KennedyJL (2011). Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders. PLoS One 6, e20982.
WangK, ZhangH, MaD, BucanM, GlessnerJT, AbrahamsBS, SalyakinaD, ImielinskiM, BradfieldJP, SleimanPM, KimCE, HouC, FrackeltonE, ChiavacciR, TakahashiN, SakuraiT, RappaportE, LajonchereCM, MunsonJ, EstesA, KorvatskaO, PivenJ, SonnenblickLI, Alvarez RetuertoAI, HermanEI, DongH, HutmanT, SigmanM, OzonoffS, KlinA, OwleyT, SweeneyJA, BruneCW, CantorRM, BernierR, GilbertJR, CuccaroML, McMahonWM, MillerJ, StateMW, WassinkTH, CoonH, LevySE, SchultzRT, NurnbergerJI, HainesJL, SutcliffeJS, CookEH, MinshewNJ, BuxbaumJD, DawsonG, GrantSF, GeschwindDH, Pericak-VanceMA, SchellenbergGD, HakonarsonH (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528533.
WechslerD (1997 a). Wechsler Adult Intelligence Test, 3rd edn (WAIS-III). Harcourt Assessment: San Antonio.
WechslerD (1997 b). Wechsler Memory Scale, 3rd edn (WAIS-III). The Psychological Corporation: San Antonio.
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