Splitting Schizophrenia: Periodic Catatonia–Susceptibility Locus on Chromosome 15q15

Abstract

The nature of subtypes in schizophrenia and the meaning of heterogeneity in schizophrenia have been considered a principal controversy in psychiatric research. We addressed these issues in periodic catatonia, a clinical entity derived from Leonhard's classification of schizophrenias, in a genomewide linkage scan. Periodic catatonia is characterized by qualitative psychomotor disturbances during acute psychotic outbursts and by long-term outcome. On the basis of our previous findings of a lifetime morbidity risk of 26.9% of periodic catatonia in first-degree relatives, we conducted a genome scan in 12 multiplex pedigrees with 135 individuals, using 356 markers with an average spacing of 11 cM. In nonparametric multipoint linkage analyses (by GENEHUNTER-PLUS), significant evidence for linkage was obtained on chromosome 15q15 (P = 2.6 x 10(-5); nonparametric LOD score [LOD*] 3.57). A further locus on chromosome 22q13 with suggestive evidence for linkage (P = 1.8 x 10(-3); LOD* 1.85) was detected, which indicated genetic heterogeneity. Parametric linkage analysis under an autosomal dominant model (affecteds-only analysis) provided independent confirmation of nonparametric linkage results, with maximum LOD scores 2.75 (recombination fraction [theta].04; two-point analysis) and 2.89 (theta =.029; four-point analysis), at the chromosome 15q candidate region. Splitting the complex group of schizophrenias on the basis of clinical observation and genetic analysis, we identified periodic catatonia as a valid nosological entity. Our findings provide evidence that periodic catatonia is associated with a major disease locus, which maps to chromosome 15q15.

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 ).…”

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

“…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 ). This linkage has been replicated in several other populations including African Americans, 31 Germans, 32 Southern African Bantu families 34 and Taiwanese.…”

“…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.…”

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

“…12 Likewise, Takahashi et al 13 reported suggestive linkage to D22S1169 in subsets of highly familial SZ pedigrees, and a genome scan of catatonic SZ pedigrees found a maximal multipoint LOD score of 2.59 at D22S1169. 14 In BPD linkage has mostly been reported (and examined) at more centromeric regions. In the study of Kelsoe et al, 15 the most significant linkage was found at D22S278 (22q12.3), but positive LOD scores (0.58- 1.22) were also reported at the most telomeric markers tested at 22q13.2-q13.…”