Molecular genetics of schizophrenia: A review of the recent literature

Current Opinion in Psychiatry

Volumn 16, Issue 2, 2003, Pages 157-170

  Levinson, Douglas F ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Candidate genes; Genetic association; Genetic linkage; Genetics; Schizophrenia

Indexed keywords

AMINO ACID OXIDASE; BINDING PROTEIN; CATECHOL METHYLTRANSFERASE; DYSBINDIN; NEU DIFFERENTIATION FACTOR; PROLINE DEHYDROGENASE; UNCLASSIFIED DRUG;

AUTOPSY; BRAIN DEVELOPMENT; CHROMOSOME 10P; CHROMOSOME 13Q; CHROMOSOME 15Q; CHROMOSOME 1Q; CHROMOSOME 22Q; CHROMOSOME 2Q; CHROMOSOME 5Q; CHROMOSOME 6P; CHROMOSOME 6Q; CHROMOSOME 8P; CHROMOSOME MAP; DNA MICROARRAY; GENE FUNCTION; GENE LINKAGE DISEQUILIBRIUM; GENE MAPPING; GENE MUTATION; GENETIC SUSCEPTIBILITY; HUMAN; HYPOTHESIS; MOLECULAR GENETICS; NEUROTRANSMISSION; PATHOGENESIS; PHENOTYPE; REVIEW; SCHIZOPHRENIA;

EID: 0037335171     PISSN: 09517367     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001504-200303000-00004     Document Type: Review

References (161)

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4. Paunio T, Ekelund J, Varilo T, et al. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 2001; 10:3037-3048. Two genome scans are reported, one of 163 families (191 ASPs) from the general Finnish population, and one of 47 nuclear families (approximately 60 ASPs) from an isolated, inbred region. Results for chromosome 1q are reported in Ref. [32]. Significant findings were observed on very distal 2q (isolate sample) and 5q31 (national sample).
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68. Ohtsuki T, Toru M, Arinami T. Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia. Psychiatr Genet 2001; 11:79-83. No association was observed between schizophrenia and GRM4 (metabotropic glutamate receptor 4, 6p21.2), using nine newly discovered sequence variants, in Japanese cases and controls.
69. Shibata H, Joo A, Fujii Y, et al. Association study of polymorphisms in the GluR5 kainate receptor gene (GRIK1) with schizophrenia. Psychiatr Genet 2001; 11:139-144. No association was observed between schizophrenia and GRIK1 (ionotropic glutamate receptor kainate 1, 21q22.11) using three new and three previously described SNPs in approximately 200 Japanese cases and controls per analysis.
70. Joo A, Shibata H, Ninomiya H, et al. Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia. Mol Psychiatry 2001; 6:186-192. No association was observed between schizophrenia and GRM2 (metabotropic glutamate receptor 2, 3p12-p11) in 213 Japanese cases and 220 controls.
71. Blackwood DHR, Fordyce A, Walker MT, et al. Schizophrenia and affective disorders - cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and p300 findings in a family. Am J Hum Genet 2001; 69:428-433.
72. Millar JK, Christie S, Anderson S, et al. Genomic structure and localisation within a linkage hotspot of Disrupted in Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001; 6:173-178. This is the initial report on the genes DISC1 and DISC2 (parallel antisense genes) found in the 1q breakpoint region of a (1;11) (q42.1; q14.3) translocation that segregates with schizophrenia and other psychiatric disorders in a large Scottish pedigree.
73. Devon RS, Anderson S, Teague PW, et al. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11:71-78. Two plausible candidate genes for schizophrenia were discovered in the breakpoint of a (1;11) (q42.1; q14.3) translocation that segregates with schizophrenia and other psychiatric disorders in a previously described very large Scottish pedigree. Although association with schizophrenia was not observed for the SNPs described here in these genes, these genes may be of importance given that this is one of the few relevant cytogenetic findings in schizophrenia.
74. Semple CA, Devon RS, Le Hellard S, Porteous DJ. Identification of genes from a schizophrenia-linked translocation breakpoint region. Genomics 2001; 73:123-126. This paper describes the possible schizophrenia candidate genes in the breakpoint region on chromosome 11, for the 1;11 breakpoint described in this group's papers on the 1q breakpoint region. No association data for schizophrenia are presented.
75. Maziade M, Fournier A, Phaneuf D, et al. Chromosome 1q12-q22 linkage results in eastern Quebec families affected by schizophrenia. Am J Med Genet 2002; 114:51-55. Linkage was not observed on proximal chromosome 1q in 21 large French Canadian pedigrees.
76. Imamura A, Tsujita T, Kayashima T, et al. Lack of association between the hKCa3 gene and Japanese schizophrenia patients. Psychiatr Genet 2001; 11:227-229. No association was observed between schizophrenia and a CAG repeat in KCNN3 (1q21.2) in 112 Japanese cases and 102 controls.
77. Ritsner M, Modai I, Ziv H, et al. An association of CAG repeats at the KCNN3 locus with symptom dimensions of schizophrenia. Biol Psychiatry 2002; 51:788-794. Longer alleles of the CAG repeat in KCNN3 (1q21.2) predicted a greater severity of negative symptoms and of paranoid symptoms and an earlier age at onset in 117 Israeli cases (P<0.001 overall multivariate analysis of variance).
78. Boin F, Zanardini R, Pioli R, et al. Association between G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry 2001; 6:79-82. In 84 patients versus 138 controls, modest association (P=0.0024) is reported between schizophrenia and an SNP in TNF2A (tumor necrosis factor alpha) in 6p21.1-21.3, the most centromeric portion of the rather broad candidate region on 6p.
79. Wei J, Hemmings GP. The NOTCH4 locus is associated with susceptibility to schizophrenia. Nat Genet 2000; 25:376-377.
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82. Fan JB, Tang JX, Gu NF, et al. A family-based and case-control association study of the NOTCH4 gene and schizophrenia. Mol Psychiatry 2002; 7:100-103. No association was observed between schizophrenia and NOTCH4 SNPs in 544 Han Chinese cases and 621 controls, as well as an analysis of over 300 trios.
83. Imai K, Harada S, Kawanishi Y, et al. The (CTG)n polymorphism in the NOTCH4 gene is not associated with schizophrenia in Japanese individuals. BMC Psychiatry 2001; 1:1. No association was observed between schizophrenia and NOTCH4 SNPs in 102 Japanese cases versus 100 controls.
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86. Matsumoto S, Sasaki T, Imamura A, et al. HLA class I distribution in Japanese patients with schizophrenia. Am J Med Genet 2002; 114:42-45. No association was observed between schizophrenia and any of 45 class I HLA alleles (i.e. the lowest uncorrected P value was 0.01), in 98 Japanese cases versus 393 controls.
87. Li T, Underhill J, Liu XH, et al. Transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios from a Han Chinese population. Schizophr Res 2001; 49:73-78. In 165 Han Chinese proband-parent trios, no significant association of HLA DRB1, DQA1, DQB or DPB alleles or haplotypes was observed after correction for multiple tesing (the lowest global P value was 0.019).
88. Blaveri E, Kalsi G, Lawrence J, et al. Genetic association studies of schizophrenia using the 8p21-22 genes: prepronociceptin (PNOC), neuronal nicotinic cholinergic receptor alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1). Eur J Hum Genet 2001; 9:469-472. No association with schizophrenia was observed for markers in three genes in the 8p21-22 region implicated by schizophrenia linkage studies.
89. 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.
90. Freedman R, Adams CE, Adler LE, et al. Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. Am J Med Genet 2000; 97:58-64.
91. Freedman R, Adams CE, Leonard S. The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 2000; 20:299-306.
92. Freedman R, Leonard S, Gault JM, et al. Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alphaT-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001; 105:20-22.
93. Freedman R, Leonard S, Olincy A, et al. Evidence for the multigenic inheritance of schizophrenia. Am J Med Genet 2001; 105:794-800. The authors re-analysed all families from the NIMH Genetics Initiative schizophrenia project, combining European and African-American pedigrees (they had previously been separately analysed) and using a parametric analysis under a dominant transmission. Significant linkage was observed on chromosome 15q near the CHRNA7 locus.
94. Liu CM, Hwu HG, Lin MW, et al. Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13-14 in Taiwanese families. Am J Med Genet 2001; 105:658-661. Suggestive evidence for linkage was observed to markers near CHRNA7 (P=0.0003 and 0.0008 under broad and narrow diagnostic models by NPL analysis) in 52 Taiwanese schizophrenia families.
95. Tsuang DW, Skol AD, Faraone SV, et al. Veterans Affairs Cooperative Study. Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample. Am J Med Genet 2001; 105:662-668. Modest evidence for linkage to markers near CHRNA7 on chromosome 15q was observed in 166 schizophrenia families (216 affected sib-pairs), with a maximum NPL score of 1.65.
96. Gejman PV, Sanders AR, Badner JA, et al. Linkage analysis of schizophrenia to chromosome 15. Am J Med Genet 2001; 105:789-793. Modest evidence for linkage to markers near CHRNA7 on chromosome 15q was observed in 68 schizophrenia families with a maximum lod score (Genehunter Plus) of 2.0.
97. Xu J, Pato MT, Torre CD, et al. Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. Am J Med Genet 2001; 105:669-674. An association between CHRNA7 and schizophrenia was observed in 31 families from the Azores, with P=0.0004 for one marker. Differences related to paternally and maternally transmitted alleles were also observed. The small sample size limits the interpretation of these findings.
98. Meyer J, Ortega G, Schraut K, et al. Exclusion of the neuronal nicotinic acetylcholine receptor alpha7 subunit gene as a candidate for catatonic schizophrenia in a large family supporting the chromosome 15q13-22 locus. Mol Psychiatry 2002; 7:220-223. These authors had observed linkage between the region of 15q containing CHRNA7 and an alternative phenotype (periodic catatonia), but assocation with markers in CHRNA7 was not observed.
99. Arinami T, Ohtsuki T, Takase K, et al. Screening for 22q11 deletions in a schizophrenia population. Schizophr Res 2001; 52:167-170. Of 300 Japanese schizophrenia patients, one had a 22q11.2 (VCFS) deletion, with no obvious stigmata of VCFS.
100. De Luca A, Pasini A, Amati F, et al. Association study of a promoter polymorphism of UFD1L gene with schizophrenia. Am J Med Genet 2001; 105:529-533. In 88 patients and 92 controls from Italy, evidence for the association of schizophrenia with UFD1L was observed (P=0.009 for the variant allele), with a modest confirmation (P=0.03) in 38 proband-parent trios from Canada. This is an ubiquitin family gene in the VCFS deletion region.
101. Saito T, Guan F, Papolos DF, et al. Polymorphism in SNAP29 gene promoter region associated with schizophrenia. Mol Psychiatry 2001; 6:193-201. A modest association (P=0.009) was observed for SNAP29 (a gene in the VCFS deletion region) and schizophrenia, but not bipolar disorder.
102. Takase K, Ohtsuki T, Migita O, et al. Association of ZNF74 gene genotypes with age-at-onset of schizophrenia. Schizophr Res 2001; 52:161-165. Association (P<0.0001) is reported here for age at onset of schizophrenia (but not schizophrenia) with SNPs in the ZNF74 gene in 22q11.2 in the VCFS deletion region, in 300 Japanese cases versus 300 controls, and the finding was replicated in a second sample of 169 schizophrenia patients (P=0.0001), making this one of the few findings replicated in samples this large.
103. Feinstein C, Eliez S, Blasey C, Reiss AL. Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 2002; 51:312-318. The authors compared 28 children with VCFS with 29 children with comparable cognitive function, and found similar behavioral and psychiatric disorders. They suggest that the specificity of the association of schizophrenia with the VCFS deletion is unproved. However, they fail to account for the high rate of schizophrenia in adults with VCFS, certainly higher than in other groups with mild mental retardation.
104. Meyer J, Huberth A, Ortega G, et al. A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree. Mol Psychiatry 2001; 6:302-306. These authors had reported linkage of periodic catatonia (a phenotypic variant of schizophrenia) to chromosome 22q13. Here they report the co-segregation of a missense mutation in WKL1 (22q13.33) with the disorder in one extended pedigree.
105. Devaney JM, Donarum EA, Brown KM, et al. No missense mutation of WKL1 in a subgroup of probands with schizophrenia. Mol Psychiatry 2002; 7:419-423. A negative study of the association of schizophrenia with the WKL1 gene on 22q13.33, a region where linkage had been reported to the periodic catatonia phenotype.
106. Jorgensen TH, Borglum AD, Mors O, et al. Search for common haplotypes on chromosome 22q in patients with schizophrenia or bipolar disorder from the Faroe Islands. Am J Med Genet 2002; 114:245-252. This is a report on progress towards finding shared haplotypes on chromosome 22q in schizophrenia cases from a population isolate. No missense mutations were found in WKL1, a gene in the region of interest in these families.
107. McQuillin A, Kalsi G, Moorey H, et al. A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia. Eur J Hum Genet 2002; 10:491-494.
108. Gross J, Grimm O, Ortega G, et al. Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family. Psychiatr Genet 2001; 11:197-200. A negative association study in periodic catatonia (a phenotypic variant of schizophrenia) for a 22q13.3 gene.
109. Mimmack ML, Ryan M, Baba H, et al. Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22. Proc Natl Acad Sci U S A 2002; 99:4680-4685. This is an intriguing study. A custom-made microarray was used to screen brains of schizophrenia and control subjects for differences in expression. Upregulation was detected for APOL1 (apolipoprotein L1) (2.6-fold), a finding that was then replicated in a second brain collection. APOL2 and APOL4 were then shown to be similarly upregulated in two brain collections. All of these loci are in 22q12, near but not in the VCFS region.
110. Tachikawa H, Harada S, Kawanishi Y, et al. Linked polymorphisms (-333G>T and -286A>G) in the promoter region of the CCK-A receptor gene may be associated with schizophrenia. Psychiatry Res 2001; 103:147-155. Association is reported between schizophrenia and linked polymorphisms in the CCKAR promoter region.
111. Wang Z, Wassink T, Andreasen NC, Crowe RR. Possible association of a cholecystokinin promoter variant to schizophrenia. Am J Med Genet 2002; 114:479-482. Modest association (P<0.05 in several tests) was reported between schizophrenia and a polymorphism in the CCK promoter region, in 85 cases versus 247 controls, and in 60 trios (from the same cases).
112. Hattori E, Yamada K, Toyota T, et al. Association studies of the CT repeat polymorphism in the 5′ upstream region of the cholecystokinin B receptor gene with panic disorder and schizophrenia in Japanese subjects. Am J Med Genet 2001; 105:779-782.
113. Yoshikawa T, Kikuchi M, Saito K, et al. Evidence for association of the myoinositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. Mol Psychiatry 2001; 6:202-210. Association (P=0.031-0.0001) was reported between schizophrenia and three SNPs in myo-inositol monophosphatase 2 (IMPA2, 18p11.2), in 302 Japanese schizophrenia cases versus 308 controls and 205 affective disorder cases.
114. Jun TY, Pae CU, Chae JH, et al. Polymorphism of CTLA-4 gene at position 49 of exon 1 may be associated with schizophrenia in the Korean population. Psychiatry Res 2002; 110:19-25. CTLA4 (cytotoxic T-lymphocyte antigen-4, 2q33) was studied in 116 cases versus 149 controls from Korea, based on an immune hypothesis. Modest evidence for association was reported (P=0.003 for alleles).
115. Ohtsuki T, Sakurai K, Dou H, et al. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 2001; 6:211-216. Although only modest evidence of association (P=0.004 for homozygosity of linked SNPs) was reported between schizophrenia and GRIN2B (12p12), the NMDA receptor 2B, the sample size of 268 Japanese cases and 337 controls makes the study of some interest in generating hypotheses.
116. Maes M, Delanghe J, Bocchio Chiavetto L, et al. Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16. Psychiatry Res 2001; 104:1-9. Modest association is reported between schizophrenia and Hp (haptoglobin, 16q22.1), in 98 schizophrenia cases compared with established genotype and plasma level distributions in this northern Italian population. The authors present a brief but useful summary of evidence for involvement in the inflammatory system in schizophrenia; Hp is one of the acute phase inflammatory reaction proteins.
117. Hong CJ, Tsai SJ, Wang YC. Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders. Schizophr Res 2001; 49:59-63. Association between schizophrenia and the A218C polymorphism in TPH (tryptophan hydroxylase, 11p14-p15.3) was observed (P=0.002) in 196 Han Chinese cases versus 251 controls. This is the rate-limiting enzyme for serotonin biosynthesis.
118. Chen CH, Hung CC, Wei FC, Koong FJ. Debrisoquine 4-hydroxylase (CYP2D6) genetic polymorphisms and susceptibility to schizophrenia in Chinese patients from Taiwan. Psychiatr Genet 2001; 11:153-155.
119. Chiu HJ, Wang YC, Chen JY, et al. Association study of the p53-gene Pro72Arg polymorphism in schizophrenia. Psychiatry Res 2001; 105:279-283.
120. Chowdari KV, Brandstaetter B, Semwal P, et al. Association studies of cytosolic phospholipase A2 polymorphisms and schizophrenia among two independent family-based samples. Psychiatr Genet 2001; 11:207-212.
121. Ishiguro H, Ohtsuki T, Okubo Y, et al. Association analysis of the pituitary adenyl cyclase activating peptide gene (PACAP) on chromosome 18p11 with schizophrenia and bipolar disorders. J Neural Transm - Gen Sect 2001; 108:849-854.
122. Ishiguro H, Okubo Y, Ohtsuki T, et al. Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence. Am J Med Genet 2002; 114:15-23.
123. Jun TY, Pae CU, Chae JH, et al. Report on IL-10 gene polymorphism at position 819 for major depression and schizophrenia in Korean population. Psychiatr Clin Neurosci 2002; 56:177-180.
124. Chiavetto LB, Boin F, Zanardini R, et al. Association between promoter polymorphic haplotypes of interleukin-10 gene and schizophrenia. Biol Psychiatry 2002; 51:480-484.
125. Kunugi H, Kato T, Fukuda R, et al. Association study of C825T polymorphism of the G-protein b3 subunit gene with schizophrenia and mood disorders. J Neural Transm - Gen Sect 2002; 109:213-218.
126. Lee K, Kunugi H, Nanko S. Glial cell line-derived neurotrophic factor (GDNF) gene and schizophrenia: polymorphism screening and association analysis. Psychiatr Res 2001; 104:11-17.
127. Leroy S, Griffon N, Bourdel MC, et al. Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet 2001; 105:749-752.
128. Matsumoto C, Ohmori O, Hori H, et al. Analysis of association between the Gln192Arg polymorphism of the paraoxonase gene and schizophrenia in humans. Neurosci Lett 2002; 321:165-168.
129. Ouyang WC, Wang YC, Hong CJ, Tsai SJ. Estrogen receptor alpha gene polymorphism in schizophrenia: frequency, age at onset, symptomatology and prognosis. Psychiatr Genet 2001; 11:95-98.
130. Ventriglia M, Bocchio Chiavetto L, Bonvicini C, et al. Allelic variation in the human prodynorphin gene promoter and schizophrenia. Neuropsychobiology 2002; 46:17-21.
131. Segman RH, Shapira Y, Modai I, et al. Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. Am J Med Genet 2002; 114:310-314.
132. Zhang B, Tan Z, Zhang C, et al. Polymorphisms of chromogranin B gene associated with schizophrenia in Chinese Han population. Neurosci Lett 2002; 323:229-233.
133. Hattori M, Kunugi H, Akahane A, et al. Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia. Am J Med Genet 2002; 114:304-309.
134. Leszczynska-Rodziewicz A, Czerski PM, Kapelski P, et al. A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association. Neuropsychobiology 2002; 45:182-185.
135. Feng J, Zheng J, Gelernter J, et al. An in-frame deletion in the alpha (2C) adrenergic receptor is common in African-Americans. Mol Psychiatry 2001; 6:168-172.
136. Frieboes RM, Moises HW, Gattaz WF, et al. Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2. Am J Med Genet 2001; 105:245-249.
137. Tuulio-Henriksson A, Haukka J, Partonen T, et al. Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet 2002; 114:483-490. Based on data from 264 schizophrenia patients and their relatives from a genetically isolated region in Finland, the authors suggest that measures of working memory show strong heritability, perhaps as a result of a very small number of genetic loci, and could be used for mapping studies.
138. Cosway R, Byrne M, Clafferty R, et al. Neuropsychological change in young people at high risk for schizophrenia: results from the first two neuropsychological assessments of the Edinburgh High Risk Study. Psychol Med 2000; 30:1111-1121.
139. Cosway R, Byrne M, Clafferty R, et al. Sustained attention in young people at high risk for schizophrenia. Psychol Med 2002; 32:277-286. Measures of attention were not found to differentiate significantly between the relatives of schizophrenia and control subjects.
140. Steel RM, Whalley HC, Miller P, et al. Structural MRI of the brain in presumed carriers of genes for schizophrenia, their affected and unaffected siblings. J Neurol, Neurosurg Psychiatry 2002; 72:455-458. Based on a unique set of analyses of 'obligate carriers' (well individuals who are siblings of a schizophrenia patient and who also have a schizophrenic offspring), a reduced volume of the amygdalohippocampal complex is suggested to be a specific correlate of genetic risk.
141. Narr KL, Cannon TD, Woods RP, et al. Genetic contributions to altered callosal morphology in schizophrenia. J Neurosci 2002; 22:3720-3729. An upward bowing of the corpus callosum was suggested to be a neuroanatomical marker for vulnerability to schizophrenia in the co-twins of cases.
142. Egan MF, Hyde TM, Bonomo JB, et al. Relative risk of neurological signs in siblings of patients with schizophrenia. Am J Psychiatry 2001; 158:1827-1834. Neurological signs were found to be increased in the relatives of schizophrenia patients, but the low relative risk suggested that these signs might be poor markers for genetic studies.
143. Scutt LE, Chow EW, Weksberg R, et al. Patterns of dysmorphic features in schizophrenia. Am J Med Genet 2001; 105:713-723.
144. Cardno AG, Sham PC, Farmer AE, et al. Heritability of Schneider's first-rank symptoms. Br J Psychiatry 2002; 180:35-38. First-rank psychotic symptoms were shown to be heritable in twins, although less so than the categorical diagnosis of schizophrenia.
145. Cardno AG, Rijsdijk FV, Sham PC, et al. A twin study of genetic relationships between psychotic symptoms [see Comments]. Am J Psychiatry 2002; 159:539-545. Using the Maudsley twin series, the authors suggest that if schizophrenic, manic and depressive syndromes are assigned non-hierarchically, they show substantial overlap in their genetic etiology. See comment by Kendler [146•].
146. Kendler KS. Hierarchy and heritability: the role of diagnosis and modeling in psychiatric genetics. Am J Psychiatry 2002; 159:515-518. Commenting on Cardno et al. [144•], the author points out that their data are more consistent with genetic factors influencing mood syndromes in individuals with schizophrenia, rather than for genetic overlap in the etiology of schizophrenia and bipolar disorder.
147. Brown AS, Schaefer CA, Wyatt RJ, et al. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry 2002; 159:1528-1533. Using a birth cohort from which individuals with schizophrenia spectrum disorders had previously been ascertained, the authors demonstrate a small but significant relationship between advancing paternal age and the risk of these disorders, after controlling for confounding variables such as maternal age. This suggests the possibility of de-novo genetic mutations in older fathers as factors in schizophrenia.
148. Malaspina D, Corcoran C, Fahim C, et al. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet 2002; 114:299-303. Schizophrenia patients without a family history had significantly older fathers than those with a family history, supporting the hypothesis of de-novo genetic mutations in older fathers.
149. Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull 2001; 27:379-393. The author reviews neurodevelopmental disorders previously associated with de-novo germline mutations in older fathers, and discusses mechanisms by which this effect can occur, relating it to data for schizophrenia.
150. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment [Review]. [118 refs] Annu Rev Neuroscience 2002; 25:409-432. This is a comprehensive review of evidence favoring a neurodevelopmental etiology ('pathogenetic biological events are present much earrier in life than the onset of the features of the illness', p. 411). Evidence for such influences are reviewed by time period (prenatal, perinatal, childhood and adolescence). Emphasis is placed on the strength of evidence for a relationship between schizophrenia and complications during labor and delivery, and the presence of subtle behaviors that predate active illness by many years. A polygenic-multifactorial model is favored whereby genetic predisposition which alters development, gene-environment interactions that influence or trigger the genetic effects, and cumulative effects over time of the altered development, leading to a comparably stable state that is relatively difficult to alter.
151. Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the two-hit hypothesis of schizophrenia. Schizophr Bull 2001; 273:457-476 These authors argue for a 'two-hit' hypothesis of schizophrenia whereby genetic or environmental factors alter early development, and then a second factor closer to the time of onset triggers the actual disease.
152. Schiffman J, Ekstrom M, LaBrie J, et al. Minor physical anomalies and schizophrenia spectrum disorders: a prospective investigation. Am J Psychiatry 2002; 159:238-243. In this unique study, 265 children from a 1959-1961 Danish birth cohort (90 with a parent with schizophrenia, 93 with a parent with some other psychiatric disorder, and 82 with no record of a psychiatrically ill parent) had been rated for minor physical anomalies at 11-13 years of age. Psychiatric diagnosis was then determined at 31-33 years by direct interview or records. Of 131 children with three or more anomalies, 20 (15.3%) developed a schizophrenia spectrum disorder, compared with six out of 111 children with two or fewer anomalies (5.4%) (P<0.01). For the high-risk group the proportions were 12 out of 39 (30.1%) versus five out of 42 (11.9%) (P<0.04). These are striking results suggesting early, physical-developmental effects of genetic factors, although the high rate of schizophrenia spectrum disorders in this study population is a bit surprising.
153. Bassett AS, Chow EW, O'Neill S, Brzustowicz LM. Genetic insights into the neurodevelopmental hypothesis of schizophrenia. Schizophr Bull 2001; 27:417-430. This article provides a useful review of neurodevelopmental research in schizophrenia from a group that has focused on the study of classic genetic features such as physical anomalies and the VCFS syndrome.
154. DeLisi LE. Speech disorder in schizophrenia: review of the literature and exploration of its relation to the uniquely human capacity for language. Schizophr Bull 2001; 27:481-496. Based on data from a study of structured ratings of elements of language in freeform speech, the author proposes that the pathology of schizophrenia may be related to genes underlying uniquely human characteristics of language.
155. Judson R, Salisbury B, Schneider J, et al. How many SNPs does a genome-wide haplotype map require? Pharmacogenomics 2002; 3:379-391.
156. Gabriel SB, Schaffner SF, Nguyen H, et al. The structure of haplotype blocks in the human genome. Science 2002; 296:2225-2229.
157. Daly MJ, Rioux JD, Schaffner SF, et al. High-resolution haplotype structure in the human genome. Nat Genet 2001; 29:229-232.
158. Bouchie A. Haplotype map planned. Nat Biotechnol 2001; 19:704.
159. Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet 2000; 26:151-157.
160. Faham M, Baharloo S, Tomitaka S, et al. Mismatch repair detection (MRD): high-throughput scanning for DNA variations. Hum Mol Genet 2001; 10:1657-1664.
161. Conrad P. Genetic optimism: framing genes and mental illness in the news. Cult Med Psychiatry 2001; 25:225-247. The author analyzes news reports about psychiatric genetics findings and critiques the 'genetic optimism' that emphasizes the inevitability of discovering genes and the good outcomes of those discoveries, whereas negative or retracted findings receive no attention. Scientific colleagues in genetics and other fields are prone to similar distortions, as discussed in the present article.