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Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study

  • M.-H. Hall (a1), K. Schulze (a2), F. Rijsdijk (a3), S. Kalidindi (a2), C. McDonald (a4), E. Bramon (a2), R. M. Murray (a2) and P. Sham (a5)
  • DOI:
  • Published online: 01 March 2009

Impaired P300 auditory response has been reported in patients with psychotic bipolar disorder (BPD) and unaffected relatives of psychotic bipolar patients. Deficits in mismatch negativity (MMN), however, have not been observed in bipolar patients. To our knowledge, no family study of MMN in BPD has been reported. The current study combined the Maudsley twin and bipolar family samples using genetic model fitting analyses to: (1) assess the relationship between BPD and MMN, (2) substantiate the association between psychotic BPD and P300 variables, (3) verify the genetic overlap of BPD with P300 amplitude previously reported in the twin sample, and (4) examine the shared genetic influences between BPD and bilateral temporal scalp locations of P300 components.


A total of 301 subjects were included in this study, including 94 twin pairs, 31 bipolar families, and 39 unrelated healthy controls. Statistical analyses were based on structural equation modelling.


Both P300 and MMN are heritable, with heritability estimates of 0.58 for MMN, 0.68–0.80 for P300 amplitude, and 0.21–0.56 for P300 latency. The bipolar patients and their relatives showed normal MMN. No significant association, either genetic or environmental, was found with BPD. BPD was significantly associated with reduced P300 amplitude and prolonged latency on midline and bilateral temporal-posterior scalp areas. Shared genetic factors were the main source of these associations.


The results confirm that MMN is not an endophenotype for psychotic BPD whereas P300 amplitude and latency components are valid endophenotypes for psychotic BPD.

Corresponding author
*Address for correspondence: M.-H. Hall, Ph.D., Psychology Research Laboratory, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. (Email:
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L Almasy , J Blangero (2001). Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. American Journal of Medical Genetics 105, 4244.

DL Braff , R Freedman , NJ Schork , II Gottesman (2007). Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophrenia Bulletin 33, 2132.

DM Dick , K Jones , N Saccone , A Hinrichs , JC Wang , A Goate , L Bierut , L Almasy , M Schuckit , V Hesselbrock , J Tischfield , T Foroud , H Edenberg , B Porjesz , H Begleiter (2006). Endophenotypes successfully lead to gene identification: results from the collaborative study on the genetics of alcoholism. Behavior Genetics 36, 112126.

R Freedman , H Coon , M Myles-Worsley , A Orr-Urtreger , A Olincy , A Davis , M Polymeropoulos , J Holik , J Hopkins , M Hoff , J Rosenthal , MC Waldo , F Reimherr , P Wender , J Yaw , DA Young , CR Breese , C Adams , D Patterson , LE Adler , L Kruglyak , S Leonard , W Byerley (1997). Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proceedings of the National Academy of Sciences USA 94, 587592.

ES Gershon (2000). Bipolar illness and schizophrenia as oligogenic diseases: implications for the future. Biological Psychiatry 47, 240244.

II Gottesman , TD Gould (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636645.

M-H Hall , FV Rijsdijk , M Picchioni , K Schulze , U Ettinger , T Toulopoulou , R Murray , P Sham (2007 b). Substantial shared genetic influences on schizophrenia and event-related potentials. American Journal of Psychiatry 164, 804812.

M-H Hall , K Schulze , FV Rijsdijk , M Picchioni , U Ettinger , E Bramon , R Freedman , R Murray , P Sham (2006 b). Heritability and reliability of P300, P50 and duration mismatch negativity. Behavior Genetics 36, 845857.

MH Hall , K Schulze , P Sham , S Kalidindi , C McDonald , E Bramon , DL Levy , RM Murray , F Rijsdijk (2008). Further evidence for shared genetic effects between psychotic bipolar disorder and P50 suppression: a combined twin and family study. American Journal of Medical Genetics 147B, 619627.

DC Javitt , KM Spencer , GK Thaker , G Winterer , M Hajos (2008). Neurophysiological biomarkers for drug development in schizophrenia. Nature Reviews Drug Discovery 7, 6883.

RT Knight , D Scabini , DL Woods , CC Clayworth (1989). Contributions of temporal-parietal junction to the human auditory P3. Brain Research 502, 109116.

GA Light , DL Braff (2005). Mismatch negativity deficits are associated with poor functioning in schizophrenia patients. Archives of General Psychiatry 62, 127136.

GA Light , NR Swerdlow , DL Braff (2007). Preattentive sensory processing as indexed by the MMN and P3a brain responses is associated with cognitive and psychosocial functioning in healthy adults. Journal of Cognitive Neuroscience 19, 16241632.

N Martin , D Boomsma , G Machin (1997). A twin-pronged attack on complex traits. Nature Genetics 17, 387392.

P McGuffin , F Rijsdijk , M Andrew , P Sham , R Katz , A Cardno (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60, 497502.

A Meyer-Lindenberg , DR Weinberger (2006). Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nature Reviews Neuroscience 7, 818827.

WJ Muir , DM St Clair , DH Blackwood (1991). Long-latency auditory event-related potentials in schizophrenia and in bipolar and unipolar affective disorder. Psychological Medicine 21, 867879.

R Naatanen (2003). Mismatch negativity: clinical research and possible applications. International Journal of Psychophysiology 48, 179188.

MC Neale , MB Miller (1997). The use of likelihood-based confidence intervals in genetic models. Behavioral Genetics 27, 113120.

BF O'Donnell , JL Vohs , WP Hetrick , CA Carroll , A Shekhar (2004). Auditory event-related potential abnormalities in bipolar disorder and schizophrenia. International Journal of Psychophysiology 53, 4555.

A Pierson , R Jouvent , P Quintin , F Perez-Diaz , M Leboyer (2000). Information processing deficits in relatives of manic depressive patients. Psychological Medicine 30, 545555.

DF Salisbury , N Kuroki , K Kasai , ME Shenton , RW McCarley (2007). Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Archives of General Psychiatry 64, 521529.

DF Salisbury , ME Shenton , CB Griggs , A Bonner-Jackson , RW McCarley (2002). Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. Archives of General Psychiatry 59, 686694.

DF Salisbury , ME Shenton , RW McCarley (1999). P300 topography differs in schizophrenia and manic psychosis. Biological Psychiatry 45, 98106.

K Schulze , M-H Hall , C McDonald , E Bramon , N Marshall , M Walshe , R Murray (2008). Auditory P300 in patients with bipolar disorder and their unaffected relatives. Bipolar Disorder 10, 377386.

HV Semlitsch , P Anderer , P Schuster , O Presslich (1986). A solution for reliable and valid reduction of ocular artifacts, applied to the P300 ERP. Psychophysiology 23, 695703.

ME Smith , E Halgren , M Sokolik , P Baudena , A Musolino , C Liegeois-Chauvel , P Chauvel (1990). The intracranial topography of the P3 event-related potential elicited during auditory oddball. Electroencephalography and Clinical Neurophysiology 76, 235248.

VB Souza , WJ Muir , MT Walker , MF Glabus , HM Roxborough , CW Sharp , JR Dunan , DH Blackwood (1995). Auditory P300 event-related potentials and neuropsychological performance in schizophrenia and bipolar affective disorder. Biological Psychiatry 37, 300310.

RL Spitzer , J Endicott , E Robins (1978). Research diagnostic criteria: rationale and reliability. Archives of General Psychiatry 35, 773782.

D Umbricht , R Koller , L Schmid , A Skrabo , C Grubel , T Huber , H Stassen (2003). How specific are deficits in mismatch negativity generation to schizophrenia? Biological Psychiatry 53, 11201131.

DSG Umbricht , JA Bates , JA Lieberman , JM Kane , DC Javitt (2006). Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biological Psychiatry 59, 762772.

CE van Beijsterveldt , GC van Baal (2002). Twin and family studies of the human electroencephalogram: a review and a meta-analysis. Biological Psychology 61, 111138.

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