Background Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. Methods One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. Results Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM). Conclusions To our knowledge, this is the first study to suggest that genetic factors can affect performance of facial emotion perception. The findings indicate that MET variances and MET/AKT interaction may affect facial emotion perception, implicating that the MET/AKT cascade plays a significant role in facial emotion perception. Further replication studies are needed.
Ihnen GH, Penn DL, Corrigan PW, Martin J (1998) Social perception and social skill in schizophrenia. Psychiatry Res 80: 275–286.
[3]
Pinkham AE, Penn DL, Perkins DO, Graham KA, Siegel M (2007) Emotion perception and social skill over the course of psychosis: a comparison of individuals “at-risk” for psychosis and individuals with early and chronic schizophrenia spectrum illness. Cogn Neuropsychiatry 12: 198–212.
[4]
Kee KS, Horan WP, Salovey P, Kern RS, Sergi MJ, et al. (2009) Emotional intelligence in schizophrenia. Schizophr Res 107: 61–68.
[5]
Mandal MK, Pandey R, Prasad AB (1998) Facial expressions of emotions and schizophrenia: a review. Schizophr Bull 24: 399–412.
[6]
Chan RC, Li H, Cheung EF, Gong QY (2010) Impaired facial emotion perception in schizophrenia: a meta-analysis. Psychiatry Res 178: 381–390.
[7]
Kee KS, Green MF, Mintz J, Brekke JS (2003) Is emotion processing a predictor of functional outcome in schizophrenia? Schizophr Bull 29: 487–497.
[8]
Kee KS, Horan WP, Mintz J, Green MF (2004) Do the siblings of schizophrenia patients demonstrate affect perception deficits? Schizophr Res 67: 87–94.
[9]
Leppanen JM, Niehaus DJ, Koen L, Du Toit E, Schoeman R, et al. (2008) Deficits in facial affect recognition in unaffected siblings of Xhosa schizophrenia patients: evidence for a neurocognitive endophenotype. Schizophr Res 99: 270–273.
[10]
Li H, Chan RC, Zhao Q, Hong X, Gong QY (2010) Facial emotion perception in Chinese patients with schizophrenia and non-psychotic first-degree relatives. Prog Neuropsychopharmacol Biol Psychiatry 34: 393–400.
[11]
Li H, Chan RC, McAlonan GM, Gong QY (2010) Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data. Schizophr Bull 36: 1029–1039.
[12]
Rametti G, Junque C, Vendrell P, Catalan R, Penades R, et al. (2009) Hippocampal underactivation in an fMRI study of word and face memory recognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci 259: 203–211.
[13]
Barbour T, Murphy E, Pruitt P, Eickhoff SB, Keshavan MS, et al. (2010) Reduced intra-amygdala activity to positively valenced faces in adolescent schizophrenia offspring. Schizophr Res 123: 126–136.
[14]
Beevers CG, Wells TT, Ellis AJ, McGeary JE (2009) Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli. J Abnorm Psychol 118: 670–681.
[15]
Fakra E, Hyde LW, Gorka A, Fisher PM, Munoz KE, et al. (2009) Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Arch Gen Psychiatry 66: 33–40.
[16]
Iidaka T, Ozaki N, Matsumoto A, Nogawa J, Kinoshita Y, et al. (2005) A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. J Neurosci 25: 6460–6466.
[17]
Lelli-Chiesa G, Kempton MJ, Jogia J, Tatarelli R, Girardi P, et al. (2011) The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives. Psychol Med 41: 779–788.
[18]
Battaglia M, Zanoni A, Giorda R, Pozzoli U, Citterio A, et al. (2007) Effect of the catechol-O-methyltransferase val(158)met genotype on children's early phases of facial stimuli processing. Genes Brain Behav 6: 364–374.
[19]
Karam CS, Ballon JS, Bivens NM, Freyberg Z, Girgis RR, et al. (2010) Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 31: 381–390.
[20]
Kvajo M, McKellar H, Gogos JA (2010) Molecules, Signaling, and Schizophrenia. In: Swerdlow NR, editor. Behavioral Neurobiology of Schizophrenia and Its Treatment: Springer Berlin Heidelberg. pp. 629–656.
[21]
Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, et al. (1995) Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. Brain Res Mol Brain Res 32: 197–210.
[22]
Sun W, Funakoshi H, Nakamura T (2002) Localization and functional role of hepatocyte growth factor (HGF) and its receptor c-met in the rat developing cerebral cortex. Brain Res Mol Brain Res 103: 36–48.
[23]
Judson MC, Bergman MY, Campbell DB, Eagleson KL, Levitt P (2009) Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. J Comp Neurol 513: 511–531.
[24]
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4: 915–925.
[25]
Ieraci A, Forni PE, Ponzetto C (2002) Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc Natl Acad Sci U S A 99: 15200–15205.
[26]
Powell EM, Mars WM, Levitt P (2001) Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Neuron 30: 79–89.
[27]
Judson MC, Eagleson KL, Levitt P (2011) A new synaptic player leading to autism risk: Met receptor tyrosine kinase. J Neurodev Disord 3: 282–292.
[28]
Pantazopoulos H, Woo TU, Lim MP, Lange N, Berretta S (2010) Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 67: 155–166.
[29]
Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, et al. (2006) A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A 103: 16834–16839.
[30]
Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P (2008) Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res 1: 159–168.
[31]
Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, et al. (2007) Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol 62: 243–250.
[32]
Sousa I, Clark TG, Toma C, Kobayashi K, Choma M, et al. (2009) MET and autism susceptibility: family and case-control studies. Eur J Hum Genet 17: 749–758.
[33]
Dawson G, Webb SJ, McPartland J (2005) Understanding the nature of face processing impairment in autism: insights from behavioral and electrophysiological studies. Dev Neuropsychol 27: 403–424.
[34]
Sasson NJ (2006) The development of face processing in autism. J Autism Dev Disord 36: 381–394.
[35]
Dawson G, Webb SJ, Wijsman E, Schellenberg G, Estes A, et al. (2005) Neurocognitive and electrophysiological evidence of altered face processing in parents of children with autism: implications for a model of abnormal development of social brain circuitry in autism. Dev Psychopathol 17: 679–697.
[36]
Rzhetsky A, Wajngurt D, Park N, Zheng T (2007) Probing genetic overlap among complex human phenotypes. Proc Natl Acad Sci U S A 104: 11694–11699.
[37]
Burdick KE, DeRosse P, Kane JM, Lencz T, Malhotra AK (2010) Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability. Am J Psychiatry 167: 436–443.
[38]
Heuer L, Braunschweig D, Ashwood P, Van de Water J, Campbell DB (2011) Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry 1: e48.
[39]
Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, et al. (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 98: 247–252.
[40]
Hossain MA, Russell JC, Gomez R, Laterra J (2002) Neuroprotection by scatter factor/hepatocyte growth factor and FGF-1 in cerebellar granule neurons is phosphatidylinositol 3-kinase/akt-dependent and MAPK/CREB-independent. J Neurochem 81: 365–378.
[41]
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36: 131–137.
[42]
Schwab SG, Hoefgen B, Hanses C, Hassenbach MB, Albus M, et al. (2005) Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. Biol Psychiatry 58: 446–450.
[43]
Xu MQ, Xing QH, Zheng YL, Li S, Gao JJ, et al. (2007) Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population. J Clin Psychiatry 68: 1358–1367.
[44]
Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, et al. (2008) Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 118: 2200–2208.
[45]
Lin CH, Lee CC, Gean PW (2003) Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory. Mol Pharmacol 63: 44–52.
[46]
American Psychiatric Association, Task Force on DSM-IV (2000) Diagnostic and statistical manual of mental disorders : DSM-IV-TR. Washington, DC: American Psychiatric Association. xxxvii, 943 p..
[47]
Mayer JD, Salovey P, Caruso DR, Sitarenios G (2003) Measuring emotional intelligence with the MSCEIT V2.0. Emotion 3: 97–105.
Eack SM, Greeno CG, Pogue-Geile MF, Newhill CE, Hogarty GE, et al. (2010) Assessing social-cognitive deficits in schizophrenia with the Mayer-Salovey-Caruso Emotional Intelligence Test. Schizophr Bull 36: 370–380.
[50]
Lo CH, Tsai GE, Liao CH, Wang MY, Chang JP, et al. (2010) Emotional management and 5-HT2A receptor gene variance in patients with schizophrenia. Biol Psychol 83: 79–83.
[51]
Marder SR, Fenton W (2004) Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res 72: 5–9.
[52]
Kern RS, Green MF, Nuechterlein KH, Deng BH (2004) NIMH-MATRICS survey on assessment of neurocognition in schizophrenia. Schizophr Res 72: 11–19.
[53]
Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, Rodriguez-Sanchez JM, Rios-Lago M, et al. (2009) Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 15: 438–450.
[54]
Wechsler D (1997) Wechsler Adult Intelligence Scale (3rd ed). San Antonio, TX.: The psychological corporation.
[55]
Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, et al. (1998) Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry 155: 1214–1220.
[56]
Wechsler D (1997) Wechsler Memory Scale-Third edication. San Antonio, TX.: The psychological corporation.
[57]
Wechsler D (1991) Wechsler Intelligence Scale for Child (3rd ed). San Antonio, TX.: The psychological corporation.
[58]
Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, et al. (2008) The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. Am J Psychiatry 165: 214–220.
[59]
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215.
[60]
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
[61]
Pierce CA, Block RA, Aguinis H (2004) Cautionary Note on Reporting Eta-Squared Values from Multifactor ANOVA Designs. Educational and Psychological Measurement 64: 916–924.
[62]
Cohen J (1988) Statistical power analysis for the behavioral sciences. Hillsdale, N.J.: L. Erlbaum Associates. xxi, 567 p..
[63]
Erdfelder E, Faul F, Buchner A (1996) GPOWER: A general power analysis program. Behavior Research Methods 28: 1–11.
[64]
Liu YL, Fann CS, Liu CM, Wu JY, Hung SI, et al. (2006) Absence of significant associations between four AKT1 SNP markers and schizophrenia in the Taiwanese population. Psychiatr Genet 16: 39–41.
[65]
Zhou X, Xu Y, Wang J, Zhou H, Liu X, et al. (2011) Replication of the association of a MET variant with autism in a Chinese Han population. PLoS One 6: e27428.
[66]
Wilhelm O, Herzmann G, Kunina O, Danthiir V, Schacht A, et al. (2010) Individual differences in perceiving and recognizing faces-One element of social cognition. J Pers Soc Psychol 99: 530–548.
[67]
Thanseem I, Nakamura K, Miyachi T, Toyota T, Yamada S, et al. (2010) Further evidence for the role of MET in autism susceptibility. Neurosci Res 68: 137–141.
[68]
Clarke GM, Carter KW, Palmer LJ, Morris AP, Cardon LR (2007) Fine mapping versus replication in whole-genome association studies. Am J Hum Genet 81: 995–1005.
[69]
Nicodemus KK, Law AJ, Radulescu E, Luna A, Kolachana B, et al. (2010) Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. Arch Gen Psychiatry 67: 991–1001.
[70]
Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, et al. (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12: 824–828.
[71]
Hofer A, Benecke C, Edlinger M, Huber R, Kemmler G, et al. (2009) Facial emotion recognition and its relationship to symptomatic, subjective, and functional outcomes in outpatients with chronic schizophrenia. Eur Psychiatry 24: 27–32.
[72]
Edwards J, Pattison PE, Jackson HJ, Wales RJ (2001) Facial affect and affective prosody recognition in first-episode schizophrenia. Schizophr Res 48: 235–253.
[73]
Whittaker JF, Deakin JF, Tomenson B (2001) Face processing in schizophrenia: defining the deficit. Psychol Med 31: 499–507.
