Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer’s disease families.

Psychotic symptoms are frequent in late-onset Alzheimer’s disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD.

Results of the genome-wide linkage and association analyses. A) Genome-wide non-parametric two-point linkage analysis in LOAD+P (right panel) and LOAD-P families (left panel); X-axis represent each of the analyzed chromosomes and Y–axis correspond to the individual SNP’s LOD score B) Multi-point linkage analysis in chromosomal regions with genome-wide significant (two-point LOD scores evidence of linkage ≥ 3.6) in the LOAD+P families (right panel) and multi-point linkage analysis of the same chromosomes in the LOAD-P families. X-axis represent physical location in bp and Y-axis represent the individual SNP’s LOD score; C) Joint linkage and association analysis in 50kb region encompassing the linkage peak for chromosomal regions multi-point LOD scores ≥ 2.5 in the LOAD+P families. The X-axis represent represents base-pair position (Mb) along the chromosome, the left Y-axis correspond to the recombination rate (cM/Mb) and the right Y-axis correspond to the logarithm of the p-value.

The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] ​logarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients. US National Library of MedicineNational Institutes of Health

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