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Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

Zheng X, Demirci FY, Barmada MM, Richardson GA, Lopez OL, Sweet RA, Kamboh MI, Feingold E - Transl Psychiatry (2015)

Bottom Line: CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group.Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model.The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT
About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

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Related in: MedlinePlus

Manhattan plot shows the genome-wide P-values for deletion CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between deletion calls at markers (dots) and AD+P are shown using −log10P-values (vertical axis). The higher the dots are, the stronger the genetic associations are. The strongest signals are seen on chromosome 4 and chromosome 9. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.
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fig3: Manhattan plot shows the genome-wide P-values for deletion CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between deletion calls at markers (dots) and AD+P are shown using −log10P-values (vertical axis). The higher the dots are, the stronger the genetic associations are. The strongest signals are seen on chromosome 4 and chromosome 9. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.

Mentions: A Manhattan plot showing genome-wide P-values for association of AD+P with deletion CNVs is presented in Figure 3. None of the deletions is genome-wide significantly associated with AD+P. However, we identified two deletions that showed a marginal association with AD+P (P<1.0E−3). One was located on chromosome 4, which was more frequent in AD+P subjects (26.1%) than in AD intermediate P (19.6%) and AD−P (12.5%) subjects. There were no known genes in this deletion region. Another deletion we identified was located on chromosome 9p22.2 and was present only in AD+P subjects (P=8.87E−04); none of AD intermediate P or AD−P subjects had this deletion. This was a hemizygous deletion (copy number=1) and it affected only one gene, CNTLN (centlein, centrosomal protein). Detailed information on these two deletions is given in Table 3. Examples of this deletion in one CNV carrier and one subject without CNV based on LRR and BAF are shown in Figure 2.


Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

Zheng X, Demirci FY, Barmada MM, Richardson GA, Lopez OL, Sweet RA, Kamboh MI, Feingold E - Transl Psychiatry (2015)

Manhattan plot shows the genome-wide P-values for deletion CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between deletion calls at markers (dots) and AD+P are shown using −log10P-values (vertical axis). The higher the dots are, the stronger the genetic associations are. The strongest signals are seen on chromosome 4 and chromosome 9. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490277&req=5

fig3: Manhattan plot shows the genome-wide P-values for deletion CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between deletion calls at markers (dots) and AD+P are shown using −log10P-values (vertical axis). The higher the dots are, the stronger the genetic associations are. The strongest signals are seen on chromosome 4 and chromosome 9. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.
Mentions: A Manhattan plot showing genome-wide P-values for association of AD+P with deletion CNVs is presented in Figure 3. None of the deletions is genome-wide significantly associated with AD+P. However, we identified two deletions that showed a marginal association with AD+P (P<1.0E−3). One was located on chromosome 4, which was more frequent in AD+P subjects (26.1%) than in AD intermediate P (19.6%) and AD−P (12.5%) subjects. There were no known genes in this deletion region. Another deletion we identified was located on chromosome 9p22.2 and was present only in AD+P subjects (P=8.87E−04); none of AD intermediate P or AD−P subjects had this deletion. This was a hemizygous deletion (copy number=1) and it affected only one gene, CNTLN (centlein, centrosomal protein). Detailed information on these two deletions is given in Table 3. Examples of this deletion in one CNV carrier and one subject without CNV based on LRR and BAF are shown in Figure 2.

Bottom Line: CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group.Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model.The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

ABSTRACT
About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

Show MeSH
Related in: MedlinePlus