Genetic bases for endophenotypes in psychiatric disorders

Dialogues Clin Neurosci. 2005;7:95-101.

This article reviews the concept of an endophenotype, with particular reference to heritability as well as diagnostic specificity. An endophenotype need not be heritable, for example, the possible influence of in utero viral infections for schizophrenia. However, heritability is a useful characteristic for a potential endophenotype, as it can be studied in relation to a plausible candidate gene. It should be noted that the traditional methods of demonstrating heritability eg, twin studies, can be supplemented with DNA sequence studies, suggesting heritability. Endophenotypes need not be specific to a given nosological class of psychiatric disorders, as these classes do not reflect biological categories. Evidence for two useful schizophrenia endophenotypes, the P50 abnormalities and cognitive deficits, is summarized.

Author Affiliations: 
Department of Psychiatry and the Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pa, USA (Wade H. Berrettini) 
Address for correspondence: 
wadeb@mail.med.upenn.edu  

The concept of endophenotypes in psychiatric disorders has been developed over the last few decades. In their 1967 paper on the genetics of schizophrenia, Gottesman and Shields[1] used the term endophenotype to define an illness-related characteristic, observable through biochemical testing or microscopic examination. It is assumed that a valid and useful endophenotype is more closely related to one or more pathophysiological genes for the nosological category, compared with the entire spectrum of disorders included in the nosological category. The utility of endophenotypes in psychiatric research is now more appreciated because we have a more accurate understanding of the genetic complexity of operationally defined disorders in our current psychiatric nosology. Endophenotypes should be valid approaches to creating more homogeneous subtypes of current diagnostic categories. If endophenotypes can create more homogeneous subgroups of the traditional nosology of schizophrenia and affective disorders, then more rapid advances in understanding these disorders at the genetic, molecular level can be made. Improved pharmacotherapy would surely follow.

Criteria for an andophenotype

The criteria for an endophenotype have been derived from those proposed by Gershon and Goldin[2]:

In what follows below, we consider aspects of endophenotypes.

Diagnostic specificity for an endophenotype

The first criterion for an endophenotype is typically proven by demonstrating that the endophenotype is more common among unrelated people with a given nosological diagnosis compared with the general population. A related issue is diagnostic specificity. Should a single endophenotype be specific to a given nosological classification, such as schizophrenia or bipolar disorder? While such a one-to-one correspondence might make for easier comprehension of results, our current nosological system, distinguishing schizophrenia and bipolar disorders, is constructed on the basis of symptom clusters and - to a lesser extent - the course of illness. The extent to which our current nosological classification system reflects biological distinctions is an unresolved matter.

Recent research suggests considerable overlap between schizophrenia and bipolar disorder in family studies and molecular studies (for reviews, see references 3 and 4). No bipolar family study (that was conducted in an optimal manner) reports increased risk for schizophrenia among relatives of bipolar probands. Similarly, no schizophrenia family study reports increased risk for bipolar disorders among relatives of schizophrenia probands. However, several schizophrenia family studies report increased risk for recurrent unipolar depression and schizoaffective disorders among relatives of schizophrenia probands.[5],​[6],​[7],​[8] Family studies of bipolar illness show that a spectrum of mood disorders is found among the first-degree relatives of bipolar probands: bipolar I, bipolar II with major depression (hypomania and depressive episodes in the same person), schizoaffective disorders, and recurrent unipolar depression.[8],​[9],​[10],​[11],​[12],​[13] These family studies are consistent with some degree of overlap in susceptibility to recurrent unipolar depression and schizoaffective disorders for relatives of bipolar probands and relatives of schizophrenia probands. Kendler et al[7] specifically noted an increase in risk for psychotic affective disorders among the relatives of schizophrenia probands. Thus, from this family study perspective, some endophenotypes may be shared between schizophrenia and affective disorders.

Similarly, there is molecular evidence for genetic overlap in susceptibility to schizophrenia and to affective disorders (for a review, see reference 4). One promising candidate gene is the G72 locus on chromosomal region 13q32, the site of a confirmed linkage in bipolar disorder and schizophrenia.[4] G72 is a primate-specific, brainexpressed gene that activates D-amino acid oxidase.[14] D-Amino acid oxidase may control levels of D-serine, which regulates glutamatergic receptors.[15] Chumakov et al[14] identified a haplotype from G72 single nucleotide polymorphisms (without obvious functional significance) that were in linkage disequilibrium with schizophrenia in a French-Canadian sample. This has been confirmed in distinct schizophrenia populations, including Russian,[14] German,[16] Israeli,[17] and Chinese,[18] although different haplotypes have been associated in distinct ethnic populations. Similarly, in bipolar disorder, there have been several positive findings with distinct haplotypes in different populations, including American[19],[20] and German[16] bipolar samples. Thus, from this molecular perspective, some endophenotypes may be shared between schizophrenic and affective disorders.

Given what we know about the overlap in genetic susceptibility to schizophrenia and mood disorders,[4] it is entirely possible that some endophenotypes may be characteristics of both types of disorder.

Stability and heritability of an endophenotype: the P50 abnormalities as an example

Ideally, an endophenotype should be a stable, state-independent parameter. An endophenotype should be an enduring characteristic of an individual, and should be present prior to the onset of illness. Thus, increased rates of an endophenotype for schizophrenia should be detectable when studying the young adult children of schizophrenic persons. The same statement cannot be made regarding an endophenotypic study of the prepubertal children of schizophrenic individuals because it is entirely possible that the endophenotype may not be manifest until after puberty. This is particularly relevant because schizophrenia is uncommon among prepubertal children, but becomes common in young adults.

Increased rates of an endophenotype for schizophrenia should be detectable when studying the individuals who are acutely psychotic, as well as those in partial remission. Similarly, an endophenotype for bipolar disorder should be observable in the depressed, euthymic, or manic states.

These qualities render the endophenotype more easily demonstrable.

Consider one outstanding example of an endophenotype, the P50 abnormality in schizophrenia. An abnormality of the P50 auditory evoked potential is considered an endophenotype for schizophrenia.[21] The P50 wave is a positive deflection (recorded by scalp electrodes) occurring 50 ms after an auditory stimulus, typically a single click. When two such clicks are presented, with the second click occurring ~ 200 ms after the first, the amplitude of the P50 wave after the second click is reduced in comparison to the amplitude of the wave after the first click (Figure 1 ). This is considered to be an electrophysiological signature of sensory gating. In some individuals with schizophrenia, the amplitude of the p50 wave for the second click is similar to the amplitude after the first click. This is interpreted as a failure of sensory gating. This is shown in graphic form in Figure 1.

The P50 abnormality is found more often among individuals with schizophrenia, compared with controls,[22],[23] although this is not universally confirmed.[24],[25]The P50 abnormality is found more frequently among the relatives of persons with schizophrenia, compared to controls.[26],[27] It is a heritable characteristic, based on twin studies.[28],[29] Heritability is also implied by the reports that DNA sequence polymorphisms in and near the α7-nicotinic receptor subunit gene on chromosome 15 explain some of the variance in the P50 abnormality[30],​[31],​[32] The chromosome 15 location is a confirmed linkage region for schizophrenia,[33],​[34],​[35],​[36] thereby lending added confidence to this line of investigation.

While there is ample evidence that the P50 is partially under genetic control,[28],​[29],​[30],​[31],​[32] there is also substantial evidence that P50 parameters are influenced by environmental forces. For example, smoking or administration of nicotine may “normalize” an abnormal P50 test.[37],[38] The finding becomes more intriguing when it is recalled that ~80% of individuals with schizophrenia are daily smokers.[37] Additionally, there is evidence that atypical antipsychotic medications can “normalize” abnormal P50 testing.[39],​[40],​[41],​[42]

These results indicate a critical point when considering endophenotypes: environmental influences must be considered, not only as sources of variance (eg, experimental error, circadian variation, influence of personal habits such as nicotine and caffeine intake), but also as clues to mechanisms that may provide pathways from gene variants to endophenotypes, or from endophenotypes to key symptom clusters or subtypes of disorders.

To summarize the P50 endophenotype literature, there is substantial evidence that the P50 abnormality in schizophrenia fulfills generally accepted criteria for an endophenotype. Variation in or near the α7-nicotinic receptor subunit gene may explain some of the genetic variance in the P50 measurement, and additional research with this endophenotype can be expected to yield new insights into this subtype of schizophrenia.

Figure 1 The P50 abnormality in schizophrenia. In studying the P50 wave, two clicks (~70 db) ~200 ms apart are used. Usually the response to the second click is reduced in amplitude, in comparison to the response to the first click. In some persons with schizophrenia, the amplitude of response to the second click is not reduced.

Stability and heritability of an endophenotype: cognitive deficits in schizpophrenia as an example

A second endophenotype that has been studied extensively in schizophrenia is working memory. This term can be defined as the holding of information in the consciousness, in preparation for complex processing. Working memory can be assessed by multiple different mental tasks, such as N back, Wisconsin Card Sort, and reverse digit span. Deficits in working memory have been described as an endophenotype for schizophrenia (for a review, see reference 43). The fraction of individuals with schizophrenia who are designated as having abnormal working memory varies with the tests employed, the clinical population studied, and the definition of abnormal (eg, 1.5 or 2 standard deviation units below the mean for controls). If consideration is given only to studies of large numbers of cases (-100) and controls, most reports describe 25% to 50% of persons with schizophrenia as falling in the variably defined “deficit range” for working memory[44],​[45],​[46],​[47],​[48],​[49]

Several lines of evidence suggest that the working memory deficits are partly heritable. Twin studies of unaffected and discordant (for schizophrenia) monozygotic and dizygotic twin pairs indicate that genetic influences in the schizophrenia-related working memory deficits are prominent.[50],​[51],​[52],​[53] In addition, multiple studies suggest that a small fraction of the variance in working memory scores is explained by a functional variant in the catechol- O methyltransferase (COMT) gene,[54],​[55],​[56] although this finding is not observed consistently[57]

Working memory deficits are more common among the unaffected relatives (compared with controls) of schizophrenic individuals who have deficits themselves (for a review, see reference 8). The effect size for this observation is relatively small, such that substantial sample numbers are required to have adequate power. If only those studies that examined at minimum ~50 relatives and ~50 controls are considered,[58],​[59],​[60],​[61],​[62],​[63],​[64],​[65] then there is a preponderance of data suggesting that unaffected relatives (of schizophrenic individuals) have some of the neuropsychological deficits seen in affected persons. However, one must be concerned with a negative publication bias, and with the fact that a wide range of neuropsychological measures have been used, such as Wisconsin Card Sort, digit span, trailmaking, tests of verbal and spatial fluency, etc. The effect size is not large, as evidenced by the fact that multiple smaller studies have not found a significant difference between relatives of schizophrenic individuals and controls.[66],[67]

The preponderance of data suggests that neuropsychological/cognitive deficits in schizophrenia are present more often among affected persons compared with controls. There are data to indicate that the measures are heritable. Finally, most of the larger studies find that nonpsychotic relatives of schizophrenic individuals score more poorly on various neuropsychological tests compared with controls. Thus, various measures of cognitive function are valid endophenotypes for schizophrenia, on the basis of the criteria noted above.

Promising endophenotype candidates lacking heritability data

Several potential endophenotypes for affective disorders and schizophrenia lack sufficient heritability data. For example, multiple central nervous system imaging studies have revealed a failure to appropriately activate dorsolateral prefrontal cortex while performing a Wisconsin Card Sort task in some individuals with schizophrenia (for a review, see reference 68). This promising endophenotype lacks sufficient heritability data at present. Although there is some evidence that a COMT functional variant is correlated with the endophenotype,[54] there is a need for substantial data on normal monozygotic and dizygotic twins. One potentially useful endophenotype for affective disorders may be the magnetic resonance imaging finding of subcortical (white matter) hyperintensities among bipolar patients.[69],​[70],​[71],​[72],​[73],​[74],​[75],​[76],​[77] Multiple investigators have observed hyperintensities among bipolar patients more often and with greater severity, compared with control values.[69],​[70],​[71],​[72],​[73],​[74],​[75],​[76],​[77] Two metaanalyses[78],[79] of white matter hyperintensities in bipolar disorder were consistent with an odds ratio of ~3.2, suggesting that bipolar patients had a greater number of such lesions compared with age- and sex-matched controls. However, there are no genetic studies of white matter hyperintensities, so that heritability remains unknown. Complicating this limitation is the fact that the severity of white matter hyperintensities increases with age and cardiovascular disease risk factors,[80] a finding that suggests that the hyperintensity images are related to ischemia, which was an early hypothesis concerning these magnetic resonance images.[81] One hypothesis that deserves further exploration is that the ischemia producing the white matter hypertensities in bipolar disorder is related to central nervous system mitochondrial abnormalities.[82],​[83],​[84] Mitochondrial dysfunction could mimic ischemia, in that neuronal cells could be “starved” of oxygen, since the mitochondria are less than normally efficient in producing adenosine triphosphate (ATP).

Is heritability an essential criterion for an endophenotype?

Although heritability is considered to be one criterion for an endophenotype, this may not be an essential characteristic of all valid endophenotypes. For example, it has been hypothesized that viral infections in utero may be an environmental risk factor for schizophrenia,[85],​[86],​[87] although many studies have been unable to confirm this association (for a review, see reference 88). While this may be a valid endophenotype, it is difficult to consider this as a heritable characteristic, because the increase in risk after in utero infection has been documented for influenza[85],[87] and for rubella.[86] Thus, some endophenotypes may not have heritable components, but may be valid means for creating subgroups of cases. This does not mean that any means to create subgroups of patients represents an endophenotype. To subgroup schizophrenia patients as having suffered an in utero viral infection, one must first develop some biochemical test to determine if a given schizophrenic person has experienced such an infection. Once that test is in place, one can then attempt to define whether a particular genetic background of schizophrenia risk is more common among these unique cases.

REFERENCES
1. Gottesman II, Shields J A polygenic theory of schizophrenia. Proc Natl AcadSciUSA. 1967;58:199-205 [ Pub Med ]
2. Gershon ES, Goldin LR Clinical methods in psychiatric genetics. Acta Psychaitr Scand. 1986;74:113-118 [ Pub Med ]
3. Berrettini WH Bipolar disorder and schizophrenia: convergent molecular data. Neuromol Med. 2004;5:109-117 [ Pub Med ]
4. Berrettini W Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet. 2003;123C:59 [ Pub Med ]
5. Gershon ES, DeLisi LE, Hamovit J, et al. A controlled family study of chronic psychoses. Arch Gen Pscyhiatry. 1988;45:328-336 [ Pub Med ]
6. Taylor MA, Berenbaum SA, Jampala VC, Cloninger CR Are schizophrenia and affective disorder related? Preliminary data from a family study. Am J Psychiatry. 1993;150:278-285 [ Pub Med ]
7. Kendler KS, McGuire M, Gruenberg AM, O'Hare A, Spellman M, Walsh D The Roscommon family study. Arch Gen Psychiatry. 1993;50:527-540 [ Pub Med ]
8. Maier W, Lichtermann D, Minges J, et al. Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study. Arch Gen Psychiatry. 1993;50:871-883 [ Pub Med ]
9. Weissman MM, Gershon ES, Kidd KK, et al. Psychiatric disorders in the relatives of probands with affective disorder. Arch Gen Psychiatry. 1984;41:13-21 [ Pub Med ]
10. Winokur G, Coryell W, Keller M, Endicott J, Leon A A family study of manic depressive (bipolar I) disease. Is it a distinct illness separable from primary unipolar depression? Arch Gen Psychiatry. 1995;52:367-373 [ Pub Med ]
11. Winokur G, Tsuang MT, Crowe RR The Iowa 500: affective disorder in relatives of manic and depressed patients. Am J Psychiatry. 1982;139:209-212 [ Pub Med ]
12. Gershon ES, Hamovit J, Guroff JJ, et al. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry. 1982;39:1157-1167 [ Pub Med ]
13. Helzer JE, Winokur G A family interview study of male manic dépressives. Arch Gen Psychiatry. 1974;31:73-77 [ Pub Med ]
14. Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for damino acid oxidase in schizophrenia. G72 2002;99:13365-13367 [ Pub Med ]
15. Stevens ER, Esguerra M, Kim PM, et al. D-Serine and serine racemase are present in vertebrate retina and contribute to the activation of NMDA receptors. Proc Natl Acad Sci U S A. 2003;100:6789-6794 [ Pub Med ]
16. Schumacher J, Jamra RA, Freudenberg J, et al. Examination of G72 and D-amino acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. G72 2004;9:203-207 [ Pub Med ]
17. Korostishevsky M, Kaganovich M, Cholostoy A, et al. Is the G72/G30 locus associated with schizophrenia? G72/G30 2004;56:159-176 [ Pub Med ]
18. Zhou F, Li C, Duan S, et al. A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population. G72/G30 2005;73:257-261 [ Pub Med ]
19. Hattori E, Liu C, Badner JA, et al. Polymorphisms at the G72/G30 gene locus on 13q33 are associated with bipolar disorder in two independent pedigree series. G72/G30 2003;72:1131-1140 [ Pub Med ]
20. Chen YS, Akula N, Detera-Wadleigh SD, et al. Findings in an independent sample support an association between bipolar affective disorder and the G72IG30 locus on chromosome 13q33. Mol Psychiatry. 2004;9:87-92 [ Pub Med ]
21. Freedman R, Adler LE, Leonard S Alternative phenotypes for the complex genetics of schizophrenia. Biol Psychiatry. 1999;45:551-558 [ Pub Med ]
22. Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry. 1983;18:537-551 [ Pub Med ]
23. Adler LE, Pachtman E, Franks RD, Pacevich M, Waldo M, Freedman R Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry. 1982;17:639-654 [ Pub Med ]
24. Kathman N, Engel R Sensory gating in normals and schizophrenics: a failure to find strong P50 suppression in normals. Biol Psychiatry. 1990;27:1216-1226 [ Pub Med ]
25. Bramon E, Stagias K, Croft RJ, McDonald C, Murray RM The P50 waveform is normal in people with schizophrenia and their relatives. Schizophr Res. 2002;53:214 [ Pub Med ]
26. Clementz BA, Geyer MA, Braff DL Poor P50 suppression among schizophrenia patients and their first-degree biological relatives. Am J Psychiatry. 1998;155:1691-1694 [ Pub Med ]
27. Miles-Worsley M, Ord L, Blailes F, Ngiralmau H, Freedman R P50 sensory gating in adolescents from a Pacific island isolate with elevated risk for schizophrenia. Biol Psychiatry. 2004;55:663-667 [ Pub Med ]
28. Myles-Worsley M, Coon H, Byerley W, Waldo M, Young D, Freedman R Developmental and genetic influences on the P50 sensory gating phenotype. Biol Psychiatry. 1996;39:289-295 [ Pub Med ]
29. Young D, Waldo M, Rutledge JH, Freedman R Heritability of inhibitory gating of the P50 auditory evoked potential in monozygotic and dizygotic twins. Neuropsychobiology. 1996;33:113-117 [ Pub Med ]
30. Raux G, Bonnet-Brilhault F, Louchart S, et al. The 2 bp deletion in exon 6 of the α7-like nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. Mol Psychiatry. 2002;7:1006-1011 [ Pub Med ]
31. Leonard S, Gault J, Hopkins J, et al. Association of the promoter variants in the 0C7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry. 2002;59:1085-1096 [ Pub Med ]
32. Houy E, Raux G, Thibalt F, et al. The promoter -194C polymorphism of the nicotinic oc7 receptor gene has a protective effect against the P50 sensory gating deficit. Mol Psychiatry. 2004;9:320-322 [ Pub Med ]
33. 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 US A. 1997;94:587-592 [ Pub Med ]
34. Liu CM, Hwu HG, Lin MW, et al. Suggestive evidence of linkage of schizophrenia to markers at chromosome 15q13-14 in Taiwanese families. Am J Med Genet. 2001;105:658-661 [ Pub Med ]
35. Stober G, Saar K, Ruschendorf G, et al. Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. Am J Hum Genet. 2000;67:1201-1207 [ Pub Med ]
36. Freedman R, Leonard S Editorial: genetic linkage to schizophrenia at chromosome 15q14. Am J Med Genet. 2001;105:655-657 [ Pub Med ]
37. Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry. 1992;32:607-616 [ Pub Med ]
38. Adler LE, Hoffer LD, Wiser A, Freedman R Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856-1861 [ Pub Med ]
39. Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry. 1996;40:181-188 [ Pub Med ]
40. Nagamoto HT, Adler LE, McRae KA, et al. Auditory P50 in schizophrenics on clozapine: improved gating parallels clinical improvement and changes in plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology. 1999;39:10-17 [ Pub Med ]
41. Kumari V, Soni W, Sharma T Normalization of information processing deficits in schizophrenia with clozapine. Am J Psychiatry. 1999;156:1046-1051 [ Pub Med ]
42. Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry. 2000;157:767-771 [ Pub Med ]
43. Keri S, Janka Z Critical evaluation of cognitive dysfunctions as endophenotypes of schizophrenia. Acta Psychiatr Scand. 2004;110:83-91 [ Pub Med ]
44. Goldstein G, Shemansky WJ Influences on cognitive heterogeneity in schizophrenia. Schizophr Res. 1995;18:59-69 [ Pub Med ]
45. Palmer BW, Heaton RK, Paulsen JS, et al. Is it possible to be schizophrenic yet neuropsychological normal? Neuropsychology. 1997;11:437-446 [ Pub Med ]
46. Weickert TW, Goldberg TE, Gold JM, Bigelow LB, Egan MF, Weinberger DR Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry. 2000;57:907-913 [ Pub Med ]
47. Turetsky Bl, Moberg PJ, Mozley LH, et al. Memory-delineated subtypes of schizophrenia: relationship to clinical, neuroanatomical, and neurophysiological measures. Neuropsychology. 2002;16:481-490 [ Pub Med ]
48. Ke'ri S, Szendi I, Kelemen O, Benedek G, Janka Z Remitted schizophrenia-spectrum patients with spared working memory show information processing abnormalities. Eur Arch Psychiatry Clin Neurosci. 2001;251:60-65 [ Pub Med ]
49. Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol Psychiatry. 2001;50:98-107 [ Pub Med ]
50. Glahn DC, Therman S, Manninen M, et al. Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry. 2003;53:624-626 [ Pub Med ]
51. Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000;67:369-382 [ Pub Med ]
52. Goldberg TE, Torrey EF, Gold JM, Ragland JD, Bigelow LB, Weinberger DR Learning and memory in monozygotic twins discordant for schizophrenia. Psychol Med. 1993;23:71-85 [ Pub Med ]
53. Ando J, Ono Y, Wright MJ Genetic structure of spatial and verbal working memory. Behav Genet. 2001;31:615-624 [ Pub Med ]
54. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Va 1 108/1 58 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci US A. 2001;98:6917-6922 [ Pub Med ]
55. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D Afunctional polymorphism in the COMT gene and performance on a test of prefrontal cognition. COMT 2002;159:652-654 [ Pub Med ]
56. Goldberg TE, Egan MF, Gscheidle T, et al. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase VaM 58Met genotype and schizophrenia. O 2003;60:889-896 [ Pub Med ]
57. Hol BC, Wassink TH, O'Leary DS, Sheffield VC, Andreasen NC CatecholO-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry. 2005;10:1-12 [ Pub Med ]
58. Hoff , Svetina C, Maurizio AM, Crow TJ, Spokes K, DeLisi LE Familial cognitive deficits in schizophrenia. Am J Med Genet. 2005;133:43-49 [ Pub Med ]
59. Chen WJ, Liu SK, Chang CJ, Lien YJ, Chang YH, Hwu HG Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients. Am J Psychiatry. 1998;155:1214-1220 [ Pub Med ]
60. Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol Psychiatry. 2001;50:98-107 [ Pub Med ]
61. Conklin HM, Curtis CE, Katsanis J, lacono WG Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task. Am J Psychiatry. 2000;157:275-277 [ Pub Med ]
62. Gilvarry CM, Russell A, Hemsley D, Murray RM Neuropsychological performance and spectrum personality traits in the relatives of patients with schizophrenia and affective psychosis. Psychiatry Res. 2001;101:89-100 [ Pub Med ]
63. Franke P, Gansicke M, Schmitz S, Falkai P, Maier W Differential memory span - abnormal lateralization pattern in schizophrenic patients and their siblings? IntJ Psychophysiol. 1999;34:303-311 [ Pub Med ]
64. Toomey R, Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Tsuang MT Association of neuropsychological vulnerability markers in relatives of schizophrenic patients. Schizophr Res. 1998;31:89-98 [ Pub Med ]
65. Laurent A, Biloa-Tang M, Bougerol T, et al. Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives. Schizophr Res. 2000;46:269-283 [ Pub Med ]
66. Yurgelun-Todd DA, Kinney DK Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects. J Neuropsychiatry Clin Neurosci. 1993;5:294-300 [ Pub Med ]
67. Shedlack K, Lee G, Sakuma M, et al. Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia. Schizophr Res. 1997;25:43-52 [ Pub Med ]
68. Heinz A, Romero B, Gallinat J, Juckel G, Weinberger DR Molecular brain imaging and the neurobiology and genetics of schizophrenia. Pharmacopsychiatry. 2003;36(suppl 3):S152-S157 [ Pub Med ]
69. Dupont RM, Jernigan TL, Gillin JC Subcortical signal hyperintensities in bipolar patients. Psychiatry Res. 1987;21:357-358 [ Pub Med ]
70. Dupont RM, Jernigan TL, Butters N Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Arch Gen Psychiatry. 1990;47:55-59 [ Pub Med ]
71. Figiel GS, Krishnan KRR, Rao VP Subcortical hyperintensities on brain magnetic resonance imaging: a comparison of normal and bipolar subjects. J Neuropsychiatry. 1991;3:18-22 [ Pub Med ]
72. McDonald WM, Tupler LA, Marsteller FA, et al. Hyperintense lesions on magnetic resonance images in bipolar disorder. Biol Psychiatry. 1999;45:965-971 [ Pub Med ]
73. Ahn KH, Lyoo IK, Lee HK, et al. White matter hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neurosci. 2004;58:516-521 [ Pub Med ]
74. Swayze VW, Andreasen NC, Alliger RJ, Ehrhardt JC, Yuh WT Structural brain abnormalities in bipolar affective disorder. Ventricular enlargement and focal signal hyperintensities. Arch Gen Psychiatry. 1990;47:1054-1059 [ Pub Med ]
75. Aylward EH, Roberts-Twillie JV, Barta PE, et al. Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry. 1994;151:687-693 [ Pub Med ]
76. McDonald WM, Krishnan KR, Doraiswamy PM, Blazer DG Occurrence of subcortical hyperintensities in elderly subjects with mania. Psychiatry Res. 1991;40:211-220 [ Pub Med ]
77. Dupont RM, Butters N, Schafer K, Wilson T, Hesselink J, Gillin JC Diagnostic specificity of focal white matter abnormalities in bipolar and unipolar mood disorder. Biol Psychiatry. 1995;38:482-486 [ Pub Med ]
78. Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am J Psychiatry. 1995;152:1139-1144 [ Pub Med ]
79. Videbech P MRI findings in patients with affective disorder: a metaanalysis. Acta Psychiatr Scand. 1997;96:157-168 [ Pub Med ]
80. Lindgren A, Roijer A, Rudling O, et al. Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke. A population-based study. Stroke. 1994;25:929-934 [ Pub Med ]
81. Ginsberg MD, Hedley-Whyte ET, Richardson EP Jr Hypoxic-ischemic leukoencephalopathy in man. Arch Neurol. 1976;33:5-14 [ Pub Med ]
82. Kato T, Stine OC, McMahon FJ, Crowe RR Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry. 1997;42:871-875 [ Pub Med ]
83. Washizuka S, Kakiuchi C, Mori K, et al. Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder. Am J Med Genet. 2003;120B:72-78 [ Pub Med ]
84. Washizuka S, Iwamoto K, Kazuno A, et al. Association of mitochondrial complex I subunit GeneNDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health Pedigrees. Biol Psychiatry. 2004;56:483-487 [ Pub Med ]
85. Brown AS, Begg MD, Gravenstein S, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 2004;61:774-780 [ Pub Med ]
86. Brown AS, Cohen P, Harkavy-Friedman J, et al. A. E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biol Psychiatry. 2001;49:473-486 [ Pub Med ]
87. Mednick SA, Machon RA, Huttunen MO, Bonett D Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45:189-192 [ Pub Med ]
88. Bagalkote H, Pang D, Jones PB Maternal influenza and schizophrenia. Int J Ment Health. 2001;29:3-21 [ Pub Med ]