Behavior Genetics

, 36:845 | Cite as

Heritability and Reliability of P300, P50 and Duration Mismatch Negativity

  • Mei Hua Hall
  • Katja Schulze
  • Frühling Rijsdijk
  • Marco Picchioni
  • Ulrich Ettinger
  • Elvira Bramon
  • Robert Freedman
  • Robin M. Murray
  • Pak Sham
Original Paper



Event-related potentials (ERPs) have been suggested as possible endophenotypes of schizophrenia. We investigated the test–retest reliabilities and heritabilities of three ERP components in healthy monozygotic and dizygotic twin pairs.


ERP components (P300, P50 and MMN) were recorded using a 19-channel electroencephalogram (EEG) in 40 healthy monozygotic twin pairs, 19 of them on two separate occasions, and 30 dizygotic twin pairs. Zygosity was determined using DNA genotyping.


High reliabilities were found for the P300 amplitude and its latency, MMN amplitude, and P50 suppression ratio components. Intra-class correlation (ICC) = 0.86 and 0.88 for the P300 amplitude and P300 latency respectively. Reliability of MMN peak amplitude and mean amplitude were 0.67 and 0.66 respectively. P50 T/C ratio reliability was 0.66. Model fitting analyses indicated a substantial heritability or familial component of variance for these ERP measures. Heritability estimates were 63 and 68% for MMN peak amplitude and mean amplitude respectively. For P50 T/C ratio, 68% heritability was estimated. P300 amplitude heritability was estimated at 69%, and while a significant familiality effect was found for P300 latency there was insufficient power to distinguish between shared environment and genetic factors.


The high reliability and heritability of the P300 amplitude, MMN amplitude, and P50 suppression ratio components supports their use as candidate endophenotypes for psychiatric research.


Reliability ERPs Twins Genetic analysis Heritability 


  1. Adler LE, Freedman R, Ross RG, Olincy A, Waldo MC (1999) Elementary phenotypes in the neurobiological and genetic study of schizophrenia. Biol Psychiatry 46:8–18PubMedCrossRefGoogle Scholar
  2. Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R (1992) Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry 32:607–616PubMedCrossRefGoogle Scholar
  3. Blackwood DH, St Clair DM, Muir WJ, Duffy JC (1991) Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees. Arch Gen Psychiatry 48:899–909PubMedGoogle Scholar
  4. Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233–259PubMedGoogle Scholar
  5. Bramon E, Rabe-Hesketh S, Sham P, Murray RM, Frangou S (2004) Meta-analysis of the P300 and P50 waveforms in schizophrenia. Schizophr Res 70:315–329PubMedCrossRefGoogle Scholar
  6. Cadenhead KS, Light GA, Shafer KM, Braff DL (2005) P50 suppression in individuals at risk for schizophrenia: the convergence of clinical, familial, and vulnerability marker risk assessment. Biol Psychiatry 57:1504–1509PubMedCrossRefGoogle Scholar
  7. Cardno AG, Gottesman II II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet 97:12–17PubMedCrossRefGoogle Scholar
  8. Catts SV, Shelley AM, Ward PB et al (1995) Brain potential evidence for an auditory sensory memory deficit in schizophrenia. Am J Psychiatry 152:213–219PubMedGoogle Scholar
  9. Clementz BA, Blumenfeld LD, Cobb S (1997a) The gamma band response may account for poor P50 suppression in schizophrenia. Neuroreport 8:3889–3893Google Scholar
  10. Clementz BA, Geyer MA, Braff DL (1997b) P50 suppression among schizophrenia and normal comparison subjects: a methodological analysis. Biol Psychiatry 41:1035–1044CrossRefGoogle Scholar
  11. Clementz BA, Geyer MA, Braff DL (1998) Poor P50 suppression among schizophrenia patients and their first-degree biological relatives. Am J Psychiatry 155:1691–1694PubMedGoogle Scholar
  12. de Geus EJ (2002) Introducing genetic psychophysiology. Biol Psychol 61:1–10PubMedCrossRefGoogle Scholar
  13. Donchin E (1981) Presidential address, 1980. Surprise!...Surprise? Psychophysiology. 18(5):493–513, 1981 SepPubMedGoogle Scholar
  14. Escera C, Corral M-J, Yago E (2002) An electrophysiological and behavioral investigation of involuntary attention towards auditory frequency, duration and intensity changes. Cogn Brain Res 14:325–332CrossRefGoogle Scholar
  15. Escera C, Grau C (1996) Short-term replicability of the mismatch negativity. Electroencephalogr Clin Neurophysiol 100:549–554PubMedCrossRefGoogle Scholar
  16. Escera C, Yago E, Polo MD, Grau C (2000) The individual replicability of mismatch negativity at short and long inter-stimulus intervals. Clin Neurophysiol 111:546–551PubMedCrossRefGoogle Scholar
  17. First MB, Spitzer RL, Gibbon M, Williams JBW (1997) Structured clinical interview for DSM-IV axis I disorders (SCID). New York State Psychiatric, Institute Biometrics Research, New YorkGoogle Scholar
  18. Frangou S, Sharma T, Alarcon G et al (1997) The maudsley family study, II: endogenous event-related potentials in familial schizophrenia. Schizophr Res 23:45–53PubMedCrossRefGoogle Scholar
  19. Freedman R, Adler LE, Bickford P et al (1994) Schizophrenia and nicotinic receptors. Harv Rev Psychiatry 2:179–192PubMedGoogle Scholar
  20. Freedman R, Adler LE, Myles-Worsley M et al (1996) Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal subjects. Human recordings, computer simulation, and an animal model. Arch Gen Psychiatry 53:1114–1121PubMedGoogle Scholar
  21. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645PubMedCrossRefGoogle Scholar
  22. Haenschel C, Baldeweg T, Croft RJ, Whittington M, Gruzelier JH (2000) Gamma and beta frequency oscillations in response to novel auditory stimuli: acomparison of human electroencephalogram (EEG) data with in vitro models. Proc Natl Acad Sci USA 97:7645–7650PubMedCrossRefGoogle Scholar
  23. Hill SY, Shen S (2002) Neurodevelopmental patterns of visual P3b in association with familial risk for alcohol dependence and childhood diagnosis. Biol Psychiatry 51:621–631PubMedCrossRefGoogle Scholar
  24. Jasper H (1958) Report to the committee on methods of clinical examination in electroencephalography. Electroencephalogr Clin Neurophysiol 10:371–375Google Scholar
  25. Jeon YW, Polich J (2001) P300 asymmetry in schizophrenia: a meta-analysis. Psychiatry Res 104:61–74PubMedCrossRefGoogle Scholar
  26. Jessen F, Fries T, Kucharski C et al (2001) Amplitude reduction of the mismatch negativity in first-degree relatives of patients with schizophrenia. Neurosci Lett 309:185–188PubMedCrossRefGoogle Scholar
  27. Kathmann N, Frodl-Bauch T, Hegerl U (1999) Stability of the mismatch negativity under different stimulus and attention conditions. Clin Neurophysiol 110:317–323PubMedCrossRefGoogle Scholar
  28. Katsanis J, Iacono WG, McGue MK, Carlson SR (1997) P300 event-related potential heritability in monozygotic and dizygotic twins. Psychophysiology 34:47–58PubMedGoogle Scholar
  29. Kutas M, McCarthy G, Donchin E (1977) Augmenting mental chronometry: the P300 as a measure of stimulus evaluation time. Science 197:792–795PubMedCrossRefGoogle Scholar
  30. Little RJ, Rubin DB (2000) Causal effects in clinical and epidemiological studies via potential outcomes: concepts and analytical approaches. Annu Rev Public Health 21:121–145PubMedCrossRefGoogle Scholar
  31. Michie P, Innes-Brown H, Todd J, Jablensky AV (2002) Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry 52:749–758PubMedCrossRefGoogle Scholar
  32. Myles-Worsley M, Coon H, Byerley W, Waldo M, Young D, Freedman R (1996) Developmental and genetic influences on the P50 sensory gating phenotype. Biol Psychiatry 39:289–295PubMedCrossRefGoogle Scholar
  33. Naatanen R (1992) Attention and brain function. Erlbaum, Hillsdale, NJGoogle Scholar
  34. Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics and normal controls: effects of changing stimulation interval*1. Biol Psychiatry 25:549–561PubMedCrossRefGoogle Scholar
  35. Neale MC, Boker SM, Xie G, Maes HH (1999) MX; statistical modeling. VCU Box 900126, 5th edn. Department of Psychiatry, Richmond, VA 23298Google Scholar
  36. Neale MC, Cardon LR (1992) Methodology for genetic studies of twins and families. Kluwer Academic Publishers, DordrechtGoogle Scholar
  37. Neale MC, Miller MB (1997) The use of likelihood-based confidence intervals in genetic models. Behav Genet 27:113–120PubMedCrossRefGoogle Scholar
  38. Nichols RC, Bilbro WC (1966) The diagnosis of twin zygosity. Acta genet Basel 16:265–275PubMedCrossRefGoogle Scholar
  39. O’Connor S, Morzorati S, Christian JC, Li TK (1994) Heritable features of the auditory oddball event-related potential: peaks, latencies, morphology and topography. Electroencephalogr Clin Neurophysiol 92:115–125PubMedCrossRefGoogle Scholar
  40. O’Donnell BF, Hokama H, McCarley RW et al (1994) Auditory ERPs to non-target stimuli in schizophrenia: relationship to probability, task-demands, and target ERPs. Int J Psychophysiol 17:219–231PubMedCrossRefGoogle Scholar
  41. Pekkonen E, Rinne T, Naatanen R (1995) Variability and replicability of the mismatch negativity. Electroencephalogr Clin Neurophysiol 96:546–554PubMedCrossRefGoogle Scholar
  42. Polich J, Burns T (1987) P300 from identical twins. Neuropsychologia 25:299–304PubMedCrossRefGoogle Scholar
  43. Rogers TD, Deary I (1991) The P300 component of the auditory event-related potential in monozygotic and dizygotic twins. Acta Psychiatr Scand 83:412–416PubMedGoogle Scholar
  44. Segalowitz SJ, Barnes KL (1993) The reliability of ERP components in the auditory oddball paradigm. Psychophysiology 30:451–459PubMedGoogle Scholar
  45. Semlitsch HV, Anderer P, Schuster P, Presslich O (1986) A solution for reliable and valid reduction of ocular artifacts, applied to the P300 ERP. Psychophysiology 23:695–703PubMedGoogle Scholar
  46. Shelley AM, Ward PB, Catts SV, Michie PT, Andrews S, McConaghy N (1991) Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biol Psychiatry 30:1059–1062PubMedCrossRefGoogle Scholar
  47. Smith DA, Boutros NN, Schwarzkopf SB (1994) Reliability of P50 auditory event-related potential indices of sensory gating. Psychophysiology 31:495–502PubMedGoogle Scholar
  48. Tervaniemi M, Lehtokoski A, Sinkkonen J, Virtanen J, Ilmoniemi RJ, Naatanen R (1999) Test–retest reliability of mismatch negativity for duration, frequency and intensity changes. Clin Neurophysiol 110:1388–1393PubMedCrossRefGoogle Scholar
  49. Umbricht D, Koller R, Schmid L et al (2003) How specific are deficits in mismatch negativity generation to schizophrenia? Biol Psychiatry 53:1120–1131PubMedCrossRefGoogle Scholar
  50. Umbricht D, Krljes S (2005) Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res 76:1–23PubMedCrossRefGoogle Scholar
  51. van Baal GC, de Geus EJ, Boomsma DI (1998) Longitudinal study of genetic influences on ERP-P3 during childhood. Dev Neuropsychol 14:19–45CrossRefGoogle Scholar
  52. van Beijsterveldt CE, van Baal GC (2002) Twin and family studies of the human electroencephalogram: a review and a meta-analysis. Biol Psychol 61:111–138PubMedCrossRefGoogle Scholar
  53. van Beijsterveldt CE, van Baal GC, Molenaar PC, Boomsma DI, de Geus EJ (2001) Stability of genetic and environmental influences on P300 amplitude: a longitudinal study in adolescent twins. Behav Genet 31:533–543.PubMedCrossRefGoogle Scholar
  54. Waldo M, Gerhardt G, Baker N, Drebing C, Adler L, Freedman R (1992) Auditory sensory gating and catecholamine metabolism in schizophrenic and normal subjects. Psychiatry Res 44:21–32PubMedCrossRefGoogle Scholar
  55. Walhovd KB, Fjell AM (2002) One-year test-retest reliability of auditory ERPs in young and old adults. Int J Psychophysiol 46:29–40. PubMedCrossRefGoogle Scholar
  56. Weinberger DR, Egan MF, Bertolino A et al (2001) Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825–844PubMedCrossRefGoogle Scholar
  57. Weisbrod M, Hill H, Niethammer R, Sauer H (1999) Genetic influence on auditory information processing in schizophrenia: P300 in monozygotic twins. Biol Psychiatry 46:721–725PubMedCrossRefGoogle Scholar
  58. Young DA, Waldo M, Rutledge JH, Freedman R (1996) Heritability of inhibitory gating of the P50 auditory-evoked potential in monozygotic and dizygotic twins. Biol Psychiatry 33:113–117Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Mei Hua Hall
    • 1
    • 2
  • Katja Schulze
    • 2
  • Frühling Rijsdijk
    • 1
  • Marco Picchioni
    • 2
  • Ulrich Ettinger
    • 3
  • Elvira Bramon
    • 2
  • Robert Freedman
    • 4
  • Robin M. Murray
    • 2
  • Pak Sham
    • 1
    • 5
  1. 1.Social, Genetic Developmental Psychiatry Research Centre, Institute of PsychiatryKing’s College LondonLondonUK
  2. 2.Division of Psychological Medicine, Institute of PsychiatryKing’s College LondonLondonUK
  3. 3.Neuroimaging Research Group, Institute of PsychiatryKing’s College LondonLondonUK
  4. 4.Departments of Psychiatry and PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA
  5. 5.Department of PsychiatryUniversity of Hong KongHong KongChina

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