NIMH genetics initiative millennium schizophrenia consortium: Linkage analysis of African-American pedigrees

Abstract

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

“…32 Freedman et al 33 reported positive linkage of the abnormality in P50 suppression with D15S1360, a dinucleotide repeat present o120 kbp from the 5 0 end of the coding region of the alpha 7-nicotinic receptor gene (CHRNA-7), assuming an autosomal dominant mode of transmission (LOD score ¼ 5.3, Y ¼ 0.0, Po0.0001 33 ). This linkage has been replicated in several other populations including African Americans, 31 Germans, 32 Southern African Bantu families 34 and Taiwanese. 35 Several other studies have also pointed towards this region as being of significance for psychiatric disorders.…”

“…Chromosome 15q13-15 has been found to be associated with schizophrenia in genome wide scans [30][31][32] although the criteria for linkage were fulfilled in only one study using a subtype Periodic Catatonia (15q15 at position 35.3 cM, LOD score ¼ 3.57, P ¼ 2.6 Â 10 À5 ). 32 Freedman et al 33 reported positive linkage of the abnormality in P50 suppression with D15S1360, a dinucleotide repeat present o120 kbp from the 5 0 end of the coding region of the alpha 7-nicotinic receptor gene (CHRNA-7), assuming an autosomal dominant mode of transmission (LOD score ¼ 5.3, Y ¼ 0.0, Po0.0001 33 ).…”

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

“…14 Although CYP1A2 by itself has never been implicated in pathogenesis of schizophrenia, the neighboring loci (15q13-15) have all been implicated. [20][21][22][23] CYP1A2 (15q21) is located in the vicinity of nicotinic receptors CHRNA3, CHRNA5 and CHRNB4, localized at 15q24. CYP1A2 mRNA has been detected in the rat brain (cortex, cerebellum, brain stem, thalamus, hippocampus and striatum 24 ).…”

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

“…The P50 sensory gating deficit, one of the best supported endophenotypes of schizophrenia and bipolar disorder, is strongly linked to this region, 1 as are two idiopathic epilepsies. 2,3 Of the many attempts to demonstrate linkage of schizophrenia and bipolar disorder to this region, two studies showed linkage to bipolar disorder, 4,5 but several found either weak [6][7][8][9][10] or no linkage to schizophrenia. [11][12][13] Both schizophrenia and bipolar disorder have also shown association with 15q13.3 markers.…”