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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 duplication CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between duplication 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 signal is seen on chromosome 19. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.
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fig1: Manhattan plot shows the genome-wide P-values for duplication CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between duplication 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 signal is seen on chromosome 19. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.

Mentions: We conducted a genome-wide scan for CNVs associated with AD+P. The genome-wide P-values for duplication CNVs are shown in a Manhattan plot (Figure 1). We identified a duplication CNV on chromosome 19 that was genome-wide significantly protective against AD+P (odds ratio=0.42, P=7.20E−10 for the test based on ordered logistic regression). Forty-three out of 440 AD+P subjects carried this duplication (frequency=9.8%), while 172 out of 593 AD intermediate P and 33 out of 126 AD−P subjects had this duplication (frequency=29.0 and 24.3%, respectively). Although the duplication frequency is slightly higher in the intermediate group than in the AD−P subjects, the two groups are very similar and we interpret this departure from an ordered model as a function of the small sample size. It is worth noting that this result was highly significant even under the ordered model that we fit. This was a hemizygous duplication (copy number of 3). It was located on chromosome 19p13.3 and affected only one gene, APC2 (adenomatosis polyposis coli 2). Examples of this duplication in one CNV carrier and one subject without CNV based on LRR and BAF are shown in Figure 2. In addition, we detected four other duplications in which frequency was significantly lower (P<1.0E−05) in AD+P cases compared with non AD+P subjects. One was located on chromosome 16 and affected the ZFPM1 (zinc finger protein, FOG family member 1) gene; for those who carry the duplication, the odds of being AD+P versus non AD+P was 0.44 times lower than for those without this duplication (P=2.13E−07). The second duplication was located on chromosome 14 and affected the JAG2 (jagged 2) gene; the odds ratio of having AD+P in CNV carriers versus non-carriers was 0.43 (P=5.01E−07). The third duplication was on chromosome 9 and affected the SET (SET nuclear oncogene) gene; the AD+P odds ratio was 0.44 (P=1.95E−06) in CNV carriers. The fourth duplication was on chromosome 17 with AD+P odds ratio of 0.49 (P=4.25E−06) and affected no known genes. Detailed information on all five AD+P associated duplications is provided in Table 3.


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 duplication CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between duplication 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 signal is seen on chromosome 19. 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

fig1: Manhattan plot shows the genome-wide P-values for duplication CNVs associated with AD+P. This Manhattan plot demonstrates the locations across the chromosomes of the human genome (horizontal axis) where associations between duplication 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 signal is seen on chromosome 19. AD, Alzheimer's disease; CNV, copy-number variant; P, psychosis.
Mentions: We conducted a genome-wide scan for CNVs associated with AD+P. The genome-wide P-values for duplication CNVs are shown in a Manhattan plot (Figure 1). We identified a duplication CNV on chromosome 19 that was genome-wide significantly protective against AD+P (odds ratio=0.42, P=7.20E−10 for the test based on ordered logistic regression). Forty-three out of 440 AD+P subjects carried this duplication (frequency=9.8%), while 172 out of 593 AD intermediate P and 33 out of 126 AD−P subjects had this duplication (frequency=29.0 and 24.3%, respectively). Although the duplication frequency is slightly higher in the intermediate group than in the AD−P subjects, the two groups are very similar and we interpret this departure from an ordered model as a function of the small sample size. It is worth noting that this result was highly significant even under the ordered model that we fit. This was a hemizygous duplication (copy number of 3). It was located on chromosome 19p13.3 and affected only one gene, APC2 (adenomatosis polyposis coli 2). Examples of this duplication in one CNV carrier and one subject without CNV based on LRR and BAF are shown in Figure 2. In addition, we detected four other duplications in which frequency was significantly lower (P<1.0E−05) in AD+P cases compared with non AD+P subjects. One was located on chromosome 16 and affected the ZFPM1 (zinc finger protein, FOG family member 1) gene; for those who carry the duplication, the odds of being AD+P versus non AD+P was 0.44 times lower than for those without this duplication (P=2.13E−07). The second duplication was located on chromosome 14 and affected the JAG2 (jagged 2) gene; the odds ratio of having AD+P in CNV carriers versus non-carriers was 0.43 (P=5.01E−07). The third duplication was on chromosome 9 and affected the SET (SET nuclear oncogene) gene; the AD+P odds ratio was 0.44 (P=1.95E−06) in CNV carriers. The fourth duplication was on chromosome 17 with AD+P odds ratio of 0.49 (P=4.25E−06) and affected no known genes. Detailed information on all five AD+P associated duplications is provided in Table 3.

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