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author:("demirel, F.Y.")
1.  Association of APOE Polymorphisms and Stressful Life Events with Dementia in a Pakistani Population 
Neuroscience letters  2014;570:42-46.
Dementia is a major public health problem worldwide. Alzheimer’s disease (AD) is a major form of dementia and the APOE*4 allele is an established genetic risk factor for AD. Similarly, stressful life events are also associated with dementia. The objective of this study was to examine the association of APOE*4 and stressful life events with dementia in a Pakistani sample, which to our knowledge has not been reported previously. We also tested for an interaction between stressful life events and APOE*4 on dementia risk. A total of 176 subjects (61 cases and 115 controls) were recruited. All cases and healthy controls were interviewed to assess cognition, co-morbidities, history of stressful life events and demographics. Blood genotyping for the APOE polymorphism (E2/E3/E4) was performed. APOE*4 and stressful life events were each independently and significantly associated with the risk of dementia (APOE*4: P=0.00697; stressful life events: P=5.29E-09). However, we did not find a significant interaction between APOE*4 carrier status and stressful life events on risk of dementia (P=0.677). Although the sample size of this study was small, the established association of APOE*4 with dementia was confirmed the first time in a Pakistani sample. Furthermore, stressful life events were also found to be significantly associated with dementia in this population.
PMCID: PMC4059994  PMID: 24746929
dementia; Pakistan; stressful life events; APOE
2.  Genome-wide copy-number variation study of psychosis in Alzheimer's disease 
Translational Psychiatry  2015;5(6):e574-.
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.
PMCID: PMC4490277  PMID: 26035058
3.  Association of CLU and PICALM variants with Alzheimer's disease 
Neurobiology of Aging  2010;33(3):518-521.
Two recent large genome-wide association studies have reported significant associations in the CLU (APOJ), CR1 and PICALM genes. In order to replicate these findings, we examined 7 single nucleotide polymorphisms (SNPs) most significantly implicated by these studies in a large case-control sample comprising of 2,707 individuals. Principle components analysis revealed no population substructure in our sample. While no association was observed with CR1 SNPs (P=0.30–0.457), a trend of association was seen with the PICALM (P=0.071–0.086) and CLU (P=0.148–0.258) SNPs. A meta-analysis of three studies revealed significant associations with all three genes. Our data from an independent and large case-control sample suggest that these gene regions should be followed up by comprehensive resequencing to find functional variants.
PMCID: PMC3010357  PMID: 20570404
Alzheimer's disease; Genetics; Association
4.  Replication Study of Genome-Wide Associated SNPs with Late-Onset Alzheimer’s Disease 
Late-onset Alzheimer’s disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome-wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19 and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case-control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age-matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age-at-onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (p=0.002) and KCNMA1/rs16934131 (p=0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (p=0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies.
PMCID: PMC3082594  PMID: 21480501
Alzheimer’s disease; association; genome-wide association studies; replication; age-at-onset; disease duration
5.  Genome-wide association study of Alzheimer's disease 
Translational Psychiatry  2012;2(5):e117-.
In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ∼2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69–180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P=3.05E–07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples.
PMCID: PMC3365264  PMID: 22832961
Alzheimer's disease; genome-wide association study; meta-analysis; PPP1R3B; PTK2B; single-nucleotide polymorphisms
6.  Association of a Common G6PC2 Variant with Fasting Plasma Glucose Levels in Non-Diabetic Individuals 
Fasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples.
DNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination.
While no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036).
Our results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.
PMCID: PMC2855271  PMID: 20029179
Blood glucose; Plasma glucose; Fasting plasma glucose; G6PC2; Single nucleotide polymorphism; Polymorphism; rs560887

Results 1-6 (6)