Empirical and molecular genetics of periodic catatonia
Project management at the University of Würzburg:
In a genome-wide linkage study we identified periodic catatonia (MIM 605419) as a valid sub-phenotype of the schizophrenic psychoses with evidence for a major disease locus on chromosome 15q15. The disorder is characterized by qualitative hyperkinetic and akinetic psychomotor disturbances through acute psychotic episodes, and debilitating symptoms in the long term with psychomotor weakness, grimacing facial movements, and apathy. Using non-parametric statistics we obtained a LOD score = 3.57 and p = 2.6 x 10-5 (GENEHUNTER-PLUS). Parametric linkage results were in concordance with the assumption of monogenic inheritance. In a model with autosomal dominant mode of transmission with reduced penetrance a maximum LOD score of 2.75 was obtained on chromosome 15q. A second locus was identified on chromosome 22qtel which satisfied criteria for suggestive evidence for linkage and was mainly supported by a single large pedigree. In a second genome scan in a new set of four multiplex families, we confirmed mapping of a major gene locus on chromosome 15q15. Non-parametric multipoint linkage analyses identified a broad region with a maximum peak of Zall = 3.91 (p = 0.0063) and Zlr = 3.04 at D15S1234 (p = 0.0013), satisfying conventional criteria for confirmed linkage. Parametric affected-only analyses gave maximum HLOD score of 1.65 (D15S1234) with an estimated 47% of families linked. Analysis of individual families showed that one large family showed linkage while two other could be clearly excluded, confirming genetic heterogeneity. No other locus reached suggestive levels of significance. Haplotype analysis on chromosome 15 in this and previously linked families placed the susceptibility region to a 11 cM interval between marker D15S1042 and D15S659. Periodic catatonia is the first sub-phenotype of the schizophrenic psychoses with confirmed linkage despite existence of considerable genetic heterogeneity. In contrast, in the systematic catatonias heritability is very low (morbidity rate of 4.6% among first degree relatives) with evidence for exposure to midgestational infections during fetal life in etiopathogenesis.
Projekt period: from 01.1994 to 12.2020
DFG ( Be602/10-1 )