A new role for endophenotypes in the GWAS era: Functional characterization of risk variants

Harvard Review of Psychiatry

Volumn 18, Issue 1, 2010, Pages 67-74

  Hall, Mei Hua ^a,b   Smoller, Jordan W ^a  

^a MCLEAN HOSPITAL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Endophenotypes; Genomewide association studies (GWAS); Psychiatric genetics

Indexed keywords

ALZHEIMER DISEASE; ANXIETY DISORDER; ATTENTION DEFICIT DISORDER; AUTISM; BIPOLAR DISORDER; GENETIC VARIABILITY; GENETICS; GENOME ANALYSIS; MAJOR DEPRESSION; OBSESSIVE COMPULSIVE DISORDER; PHENOTYPE; PRIORITY JOURNAL; PSYCHIATRY; REVIEW; SCHIZOPHRENIA; SUBSTANCE ABUSE;

GENETIC VARIATION; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MENTAL DISORDERS; PHENOTYPE; RISK FACTORS;

EID: 74949122483     PISSN: 10673229     EISSN: 14657309     Source Type: Journal    
DOI: 10.3109/10673220903523532     Document Type: Review

References (87)

1. Smoller JW, Sheidley BR, Tsuang MT, eds. Psychiatric genetics: applications in clinical practice.Washington, DC: American Psychiatric Publishing, 2008.
2. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003;160:636-645
3. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science 2008;322:881-888
4. Ferreira MAR, O'Donovan MC, Meng YA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40: 1056-1058
5. Schulze TG, Detera-Wadleigh SD, Akula N, et al. Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry 2009;14:487-491
6. O'Donovan MC, Craddock N, Norton N, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008;40:1053-1055
7. Lencz T, Morgan TV, Athanasiou M, et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007;12:572-580
8. Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008;358:667-675
9. Burmeister M, McInnis MG, Zollner S. Psychiatric genetics: progress amid controversy. Nat Rev Genet 2008;9:527-540
10. Neale B, Ferreira MA, Medland SE, Posthuma D, eds. Statistical genetics: gene mapping through linkage and association. Oxford: Taylor & Francis, 2008.
11. Sullivan PF. Schizophrenia genetics: the search for a hard lead. Curr Opin Psychiatry 2008;21:157-160
12. Maher BS, Riley BP, Kendler KS. Psychiatric genetics gets a boost. Nat Genet 2008;40:1042-1044
13. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455:237-241
14. Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008;455:232-236
15. Craddock N, O'Donovan MC, Owen MJ. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005;42:193-204.
16. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 2002;159:539-545
17. Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull 2007;33:21-32.
18. Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and geneticmechanisms of psychiatric disorders. Nat Rev Neurosci 2006;7:818-827
19. Reitz C, Mayeux R. Endophenotypes in normal brain morphology and Alzheimer's disease: a review. Neuroscience 2009;164:174-190
20. Ponomareva NV, Korovaitseva GI, Rogaev EI. EEG alterations in non-demented individuals related to apolipoprotein E genotype and to risk of Alzheimer disease. Neurobiol Aging 2008;29:819-827
21. Durston S, Hulshoff Pol HE, Schnack HG, et al. Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings. J Am Acad Child Adolesc Psychiatry 2004;43:332-340
22. Mulder MJ, Baeyens D, Davidson MC, et al. Familial vulnerability to ADHD affects activity in the cerebellum in addition to the prefrontal systems. J Am Acad Child Adolesc Psychiatry 2008;47:68-75.
23. Goos LM, Crosbie J, Payne S, Schachar R. Validation and extension of the endophenotype model in ADHD patterns of inheritance in a family study of inhibitory control. Am J Psychiatry 2009;166:711-717
24. Doyle AE, Willcutt EG, Seidman LJ, et al. Attentiondeficit/hyperactivity disorder endophenotypes. Biol Psychiatry 2005;57:1324-1335
25. Losh M, Adolphs R, Poe MD, et al. Neuropsychological profile of autism and the broad autism phenotype. Arch Gen Psychiatry 2009;66:518-526
26. Gokcen S, Bora E, Erermis S, Kesikci H, Aydin C. Theory of mind and verbal working memory deficits in parents of autistic children. Psychiatry Res 2009;166:46-53.
27. Stein MB, Simmons AN, Feinstein JS, Paulus MP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 2007;164:318-327
28. Lonigan CJ, VaseyMW, Phillips BM, Hazen RA. Temperament, anxiety, and the processing of threat-relevant stimuli. J Clin Child Adolesc Psychol 2004;33:8-20.
29. Smoller JW, Paulus MP, Fagerness JA, et al. Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry 2008;65:298-308.
30. McDonald C, Bullmore ET, Sham PC, et al. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004;61:974-984
31. Thaker GK. Neurophysiological endophenotypes across bipolar and schizophrenia psychosis. Schizophr Bull 2008;34:760-773
32. Hall MH, Schulze K, Rijsdijk F, et al. Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study. Psychol Med 2009;2:1-11.
33. Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 2004;6:171-182
34. Brotman MA, Guyer AE, Lawson ES, et al. Facial emotion labeling deficits in children and adolescents at risk for bipolar disorder. Am J Psychiatry 2008;165:385-389
35. Frangou S,Haldane M, Roddy D, Kumari V. Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol Psychiatry 2005;58:838-839
36. Clark L, Sarna A, Goodwin GM. Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression. Am J Psychiatry 2005;162:1980-1982 (Pubitemid 41428635)
37. Vazquez GH, Kahn C, Schiavo CE, et al. Bipolar disorders and affective temperaments: a national family study testing the "endophenotype" and "subaffective" theses using the TEMPS-A Buenos Aires. J Affect Disord 2008;108:25-32.
38. Christensen MV, Kyvik KO, Kessing LV. Cognitive function in unaffected twins discordant for affective disorder. Psychol Med 2006;36:1119-1129
39. ChristensenMV, Kessing LV. Do personality traits predict first onset in depressive and bipolar disorder? Nord J Psychiatry 2006;60:79-88.
40. Kendler KS, Gardner CO, Prescott CA. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry 1999;56:322-327
41. Menzies L, Achard S, Chamberlain SR, et al. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain 2007;130:3223-3236
42. Menzies L, Williams GB, Chamberlain SR, et al. White matter abnormalities in patients with obsessive-compulsive disorder and their first-degree relatives. Am J Psychiatry 2008;165:1308-1315
43. Chamberlain SR, Menzies L, Hampshire A, et al. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 2008;321:421-422
44. Baare WF, van Oel CJ, Hulshoff Pol HE, et al. Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 2001;58:33-40.
45. Cannon TD, Gasperoni TL, van Erp TG, Rosso IM. Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies. Am J Med Genet 2001;105: 16-19
46. Narr KL, van Erp TGM, Cannon TD, et al. A twin study of genetic contributions to hippocampal morphology in schizophrenia. Neurobiol Dis 2002;11:83-95.
47. Braff DL, Greenwood TA, Swerdlow NR, Light GA, Schork NJ. Advances in endophenotyping schizophrenia.World Psychiatry 2008;7:11-18
48. Shenton ME, Solovay MR, Holzman PS, Coleman M, Gale HJ. Thought disorder in the relatives of psychotic patients. Arch Gen Psychiatry 1989;46:897-901.
49. Siever LJ, Davis KL. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 2004;161:398-413.
50. Rangaswamy M, Porjesz B. Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes. Brain Res 2008;1235:153-171
51. Polich J, Pollock VE, Bloom FE. Meta-analysis of P300 amplitude from males at risk for alcoholism. Psychol Bull 1994;115:55-73.
52. Braff DL, Light GA. Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology (Berl) 2004;174:75-85.
53. Javitt DC, Spencer KM, Thaker GK,Winterer G, HajosM. Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov 2008;7:68-83.
54. Hasler G, DrevetsWC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006;60:93-105.
55. Dick DM, Jones K, Saccone N, et al. Endophenotypes successfully lead to gene identification: results from the collaborative study on the genetics of alcoholism. Behav Genet 2006;36:112-126
56. Freedman R, Coon H, Myles-Worsley M, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A 1997;94:587-592
57. Sullivan P, Purcell S. Analyzing genome-wide association study data: a tutorial using PLINK. In: Neale B, Ferreira MA, Medland SE, Posthuma D, eds. Statistical genetics: gene mapping through linkage and association. New York: Taylor & Francis, 2008.
58. Altshuler D, Daly M. Guilt beyond a reasonable doubt. Nat Genet 2007;39:813-815
59. Craddock N, O'Donovan MC, Owen MJ. Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry 2008;13:649-653
60. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A May 27 2009;106:9362-9367
61. Sullivan P. A framework for interpreting genome-wide association studies of psychiatric disorders. Mol Psychiatry 2009;14:10-17
62. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-678
63. Bramon E, Rabe-Hesketh S, Sham P, Murray RM, Frangou S. Meta-analysis of the P300 and P50waveforms in schizophrenia. Schizophr Res 2004;70:315-329
64. Olincy A, Martin L. Diminished suppression of the P50 auditory evoked potential in bipolar disorder subjects with a history of psychosis. Am J Psychiatry 2005;162:43-49
65. Kwon JS, O'Donnell BF, Wallenstein GV, et al. Gamma frequency-range abnormalities to auditory stimulation in schizophrenia. Arch Gen Psychiatry 1999;56:1001-1005
66. Salisbury DF, Shenton ME, McCarley RW. P300 topography differs in schizophrenia and manic psychosis. Biol Psychiatry 1999;45:98-106.
67. O'Donnell BF, Hetrick WP, Vohs JL, Krishnan GP, Carroll CA, Shekhar A. Neural synchronization deficits to auditory stimulation in bipolar disorder. Neuroreport 2004;15:1369-1372
68. Hall M-H, Rijsdijk FV, Picchioni M, et al. Substantial shared genetic influences on schizophrenia and event-related potentials. Am J Psychiatry 2007;164:804-812
69. Hall MH, Schulze K, Sham P, et al. Further evidence for shared genetic effects between psychotic bipolar disorder and P50 suppression: a combined twin and family study. Am J Med Genet B Neuropsychiatr Genet 2008;147B:619-627
70. Bramon E, McDonald C, Croft RJ, et al. Is the P300 wave an endophenotype for schizophrenia? Ameta-analysis and a family study. Neuroimage 2005;27:960-968
71. van Beijsterveldt CE, van Baal GC. Twin and family studies of the human electroencephalogram: a review and a metaanalysis. Biol Psychol 2002;61:111-138
72. Hall M-H, Schulze K, Bramon E, Murray R, Sham P, Rijsdijk FV. Genetic overlap between P300, P50 and duration mismatch negativity. Am J Med Genet B Neuropsychiatr Genet 2006;141:336-343
73. Freedman R, Waldo M, Bickford-Wimer P, Nagamoto H. Elementary neuronal dysfunctions in schizophrenia. Schizophr Res 1991;4:233-243
74. Donchin E, Coles MGH. Is the P300 component amanifestation of context updating. Behav Brain Sci 1988;11:357-374
75. Uhlhaas PJ, Haenschel C, Nikolic D, Singer W. The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull 2008;34:927-943
76. Mulert C, Juckel G, Giegling I, et al. A Ser9Gly polymorphism in the dopamine D3 receptor gene (DRD3) and event-related P300 potentials. Neuropsychopharmacology 2006;31:1335-1344
77. Gonzalez-Burgos G, Lewis DA. GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 2008;34:944-961
78. Bartos M, Vida I, Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 2007;8:45-56.
79. Freedman R, Adler LE, Bickford P, et al. Schizophrenia and nicotinic receptors. Harv Rev Psychiatry 1994;2:179-192
80. Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull 2007;33:69-94.
81. Berrettini WH. Are schizophrenic and bipolar disorders related? A review of family andmolecular studies. Biol Psychiatry 2000;48:531-538
82. Coryell W, Leon AC, Turvey C, Akiskal HS, Mueller T, Endicott J. The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J Affect Disord 2001;67:79-88.
83. Kendler KS, Karkowski LM, Walsh D. The structure of psychosis: latent class analysis of probands from the Roscommon Family Study. Arch Gen Psychiatry 1998;55:492-499
84. Rice J, Reich T, Andreasen NC, et al. The familial transmission of bipolar illness. Arch Gen Psychiatry 1987;44:441-447
85. Lewis CM, Levinson DF, Wise LH, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003;73:34-48.
86. Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002;7:405-411
87. Walker J, Curtis V, Shaw P, Murray RM. Schizophrenia and bipolar disorder are distinguishedmainly by differences in neurodevelopment. Neurotox Res 2002;4:427-436