- Email: [email protected]
ASSOCIATION STUDY OF HIGH-RISK GENETIC VARIANTS WITH ALZHEIMER'S DISEASE IN THE KOREAN ELDERLY
Poster Presentations: Monday, July 25, 2016 Lille, France; 9Institut de la Memoire et de la Maladie d’Alzheimer (IM2A), UPMC, Paris, France; 10Gerontopole, Inserm U 1027, Alzheimers Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France; 11University of Toulouse III, Toulouse, France; 12CHU Toulouse, Toulouse, France; 13Inserm UMR 1027, Toulouse, France; 14Lille University, Lille, France; 15Inserm, U1219 and Bordeaux University, Bordeaux, France; 16Bordeaux University, Bordeaux, France; 17Memory Consultation, CHU Bordeaux, Bordeaux, France; 18Bordeaux University Hospital, Bordeaux, France; 19H^opital de la Timone, Marseille, France; 20 Aix Marseille University, Marseille, France; 21H^opitaux Universitaires de Strasbourg, CMRR, Strasbourg, France; 22ICube, University of Strasbourg, Strasbourg, France; 23Memory Resources and Research Center, CHRU Gui de Chauliac, Montpellier, France; 24Inserm-UM 1183, Montpellier, France; 25 Charpennes H^ opital-Hopitaux Civils de Lyon, Villeurbanne, France; 26 CMRR Paris Nord Ile de France, Paris, France; 27University of Paris Diderot/AP-HP, PARIS, France; 28Inserm U942, Paris, France; 29Universite Paris Descartes, Sorbonne Paris Cite, EA4468, Paris, France; 30Assistance Publique-H^ opitaux de Paris, H^opital Broca, Paris, France; 31H^opital General, Dijon, France; 32Centre Memoire de Ressources et de Recherche, CHU de Nice, Nice, France; 33CNRS, UMR 7225 ICM, Paris, France; 34 Inria, Aramis Project-Team, Centre de Recherche Paris-Rocquencourt, Paris, France; 35Sorbonne Universites, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France; 36Institut du Cerveau et de la Moelle epiniere, ICM, F-75013, Paris, France; 37Inserm, U1127, F-75013, Paris, France; 38 Inserm, Bordeaux, France. Contact e-mail: carole.Dufouil@isped. u-bordeaux2.fr Background: Several genetic polymorphisms have been associated with Late Onset Alzheimer’s Disease (LOAD), but there has been limited evidence on whether these polymorphisms correlate with MRI markers of brain pathology. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also correlate with brain MRI biomarkers in a non-demented adult population. Methods: The Memento cohort has recruited, between July 2011 and June 2014, 2323 consecutive patients with either subjective cognitive complaint or Mild cognitive impairment from 28 French research memory clinics. Participants underwent an extensive neuropsychological testing, clinical examinations, biological sampling (including DNA) and standardized cerebral MRI. Automated methods for determination of global brain volumes (grey, white, cerebro-spinal fluid), hippocampal volume, white matter lesions (WML) load and cortical thickness were used. All biological samples were stored in the centralized biobank (“Laboratoire Analyse Genomique”, Lille). For 21 SNPs (APOE, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, ABCA7, CD33, HLA, PTK2B, SORL1, SLC24A4, INPP5D, MEF2C, NMEB, ZCWPW1, CELF1, FERMT2, CASS4, TREM2) from IGAP (International Genomics of Alzheimer’s disease), we evaluated associations between each SNP and each brain pathology marker using linear regression adjusting for age, gender, education and center. We also computed two genetic risk scores combining all SNPs (6 APOE) by multiplying the allele count for each polymorphism by the reported beta coefficient from IGAP. Correction for multiple testing was applied. Results: Mean baseline age was 70.4 years, 62% were female, 40% had a clinical dementia rating scale scored 0 and 30% had at least one e4 allele of APOE genotype. APOE4 allele was associated with worse MRI markers including WML load. Fourteen out of the 20 remaining SNPs were associated with at least one MRI marker. Three SNPs (NMEB, CD33 and CASS4) were associated with WML load. Associations between AD polygenic scores
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and MRI markers were significant when ApoE was included in the score. Conclusions: In the Memento cohort, several non-Apoe genes are associated with neurodegenerative and vascular brain pathology. Understanding the mechanisms underlying the association of these genes with risk for disease could provide new insights on the natural history of AD.
P2-079
ASSESSMENT OF THE KNOWN AND CANDIDATE ALZHEIMER’S DISEASE GENES IN AFRICANAMERICANS
Aurelie Nsongo, Minerva M. Carrasquillo, Xue Wang, Jeremy D. Burgess, Thuy Nguyen, Yan W. Asmann, Steven G. Younkin, Neill R. Graff-Radford, Nilufer Ertekin-Taner, Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: African-Americans (AAs) are approximately twice as likely to develop Alzheimer’s disease (AD) compared to Caucasians. However, little is known regarding the genetics of AD in this population. Genome wide association studies of AA subjects (GWAS) suggest that AD risk variants in this population are different from those for Caucasians; underlining the importance of expanding genetic studies of AD in the AA population. Moreover, to date no mutations in the APP, PSEN1 or PSEN2 genes were reported in AA AD subjects. Methods: Whole exome sequencing was performed on genomic DNA samples from 238 self-reported AA individuals recruited from the Mayo Clinic in Jacksonville Florida, including 131 individuals with a clinical diagnosis of AD and 107 cognitively normal controls. Allelic distributions were compared between the ADs and the controls using a Fisher’s exact test as well as logistic regression analysis adjusted for sex, age and APOE ε4 dosage. Results: Out of the 110,373 variants that remained after quality control, 206 were in genes previously associated with late onset AD risk in Caucasians (CASS4, FERMT2, HLA-DRB1, INPP5D, MEF2C, NME8, PTK2B, SLC24A4, SORL1, CELF1, ZCWPW1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, ABCA7, CD33, DSG2), among which 7 showed a nominally significant association with AD risk by logistic regression analysis (p-value < 0.05) and 3 showed a nominally significant association with AD risk by Fisher’s exact test (p-value < 0.05). In addition, 14 variants were in early-onset familial AD genes (APP, PSEN1, PSEN2), out of which, 6 were observed in at least one of our AD cases but never in our controls. Although residing in genes previously associated with/causative of AD in Caucasians, those specific variants have never been associated with AD risk in Caucasian studies. Conclusions: These preliminary results suggest that, while same genes and pathways may underlie the disease mechanism in both ethnic groups, different genetic variants may modulate the disease risk in AAs in comparison to Caucasians. Validation of these results in a larger AA cohort is currently underway.
P2-080
ASSOCIATION STUDY OF HIGH-RISK GENETIC VARIANTS WITH ALZHEIMER’S DISEASE IN THE KOREAN ELDERLY
Ji Su Lee1,2, Na Hyeon Kim1,2, Tamil Iniyan Gunasekaran1, Sa Rang Kang1,2, Wooje Lee1, Jang Jae Lee1, Kyu Yeong Choi1,3, Kun Ho Lee1,2,4, 1National Research Center for Dementia, Chosun
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Poster Presentations: Monday, July 25, 2016
University, Gwangju, Republic of Korea; 2Department of Life Science, Chosun University, Gwangju, Republic of Korea; 3Department of Premedics, Chosun University, Gwangju, The Republic of Korea; 4College of Natural Sciences, Chosun University, Gwangju, Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common form
of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Genome wide association studies (GWAS) in which hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested for association with a disease in hundreds or thousands of persons. Although there are several kinds of GWAS studies for AD with the Caucasian population, the studies for Asians, in particular Koreans are not sufficient. In this study, we identified several high-risk single nucleotide polymorphisms (SNPs) associated with AD in Korean population. Methods: The study consisted of 211 normal subjects and 357 AD patients from the Korean population. The two groups were further divided as 137 male and 220 female in the control group and 87 male and 124 female in the AD group respectively. The individuals aged above 50 were included to check the association with LOAD. Blood samples collected from those groups were SNP genotyped. Results: The highly AD-associated SNPs were rs4848905 (CNTNAP5) and rs75605691 (VPS13A-AS1). In addition, we performed the correlation analysis between these AD high-risk SNPs and the neuropsychological test scores in normal control group. Surprisingly, these two SNPs (rs4848905 and rs75605691) showed the strong correlations with COWAT neuropsychological assessments. Conclusions: These results suggest that the AD-risk genetic factors may cause the cognitive changes in the normal state. Taken together, the genetic variants identified in this study can serve as the potential diagnostic markers in the early diagnosis of Alzheimer’s disease.
P2-081
ASSOCIATION STUDY OF SORL1 GENE SNP RS1133174 WITH THE RISK OF AMNESTIC MILD COGNITIVE IMPAIRMENT
Chunhui Jin, Xiaowei Liu, Feng Zhang, Jianzhong Zhu, Zaohuo Cheng, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China. Contact e-mail: [email protected] Background: To explore the association of sortilin-related receptor 1 (SORL1) gene single nucleotide polymorphism (SNP) rs1133174 with the risk of amnestic mild cognitive impairment (aMCI) in the Han Chinese population. Methods: We recruited 63 aMCI patients and 179 healthy controls and genotyped the SORL1 gene SNP rs1133174 using LDR-PCR method. The association between rs1133174 and the risk of aMCI was then analyzed. Results: We found that the ‘G’ allele frequency in aMCI patients was significantly higher than that in healthy controls (OR ¼ 2.221, 95% CI ¼ 1.396-3.533, P ¼ 0.0006). A logistic regression analysis further identified that the ‘G’ allele carriers had an increased risk compared with non-carriers (GG + GA vs. AA, OR ¼2.713, 95% CI ¼ 1.4954.918, P ¼ 0.0005). Furthermore, a stratified analysis indicated that the SORL1 SNP rs1133174 might be an APOE 34-independent risk factor. Conclusions: The SORL1 gene SNP rs1133174 may be significantly associated with the risk of aMCI in the Han Chinese population.
P2-082
COMPARISON OF GENE-BASED METHODS TO IDENTIFY NOVEL ALZHEIMER’S DISEASE– ASSOCIATED GENES
Emily Ann Baker1, Valentina Escott-Price1, Rebecca Sims1, Peter Holmans1, Julie Williams1 GERAD, IGAP, 1MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Contact e-mail: [email protected] Background: Gene-based analysis may enable the determination of
novel loci associated with AD compared to single SNP analysis, since the combined effect of SNPs within genes may be captured. A novel method using polygenic risk score (PRS) is considered; this informs the analysis with previously reported effect sizes of a SNPs association to AD. Methods: GERAD data (3332 cases, 9832 controls) was used to calculate PRSs and ADGC, EADI and CHARGE data (5240 cases, 1800 controls) was used to determine effect sizes for linkage disequilibrium (LD) pruned SNPs. SNPs common to both datasets were annotated to genes. The PRS was calculated per subject per gene. Logistic regression models determined the association of the PRSgenebased for each gene with AD, accounting for population covariates. These results were compared to those produced using Fisher’s and Simes’ methods for combining p-values and the power of these methods to detect genes associated with AD were compared. We also investigated the power of our approach compared to Simes. Results: Our approach replicates the results of [1]. No novel genes have been determined, but since data was pruned, the power for the analysis to detect associated genes will likely be reduced. The PRSgenebased p-values were correlated with both Fisher’s and Simes’ p-values, with correlation strength increasing for more significant genes. Since larger genes may harbour more significant SNPs by chance, we determined the correlation between the number of SNPs per gene and the significance of a gene. There was no evidence of a significant correlation between PRSgenebased and the number of SNPs per gene (r¼-0.0054). Conclusions: In this study we applied a genebased PRS approach to LD pruned SNPs. This method will be extended for unpruned data with appropriate adjustment for LD between SNPs, thus increasing power and improving the possibility of detecting novel genes associated with AD. This method has potential to discover data-driven pathways, it may be used for prioritisation of subjects for follow-up studies (e.g. clinical trials) based upon single gene or pathway PRS, and for prioritising genes for further functional studies (e.g. animal models). [1] V.Escott-Price,C.Bellenguez,L.S.Wang,S.H.Choi,et al.,’Gene-wide analysis detects two new susceptibility genes for Alzheimer’s disease. PLoS One, vol.9,no.6,p.e94661,2014.
P2-083
COMPUTATIONAL IDENTIFICATION OF REGULATORY MECHANISMS AFFECTED BY NONCODING VARIANTS ASSOCIATED WITH LATE-ONSET ALZHEIMER’S DISEASE
Alexandre Amlie-Wolf1, Mitchell Tang1, Jessica King1, Beth A. Dombroski1, Li-San Wang2, Gerard D. Schellenberg2, 1University of Pennsylvania, Philadelphia, PA, USA; 2University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: More than 20 single nucleotide polymorphisms
(SNPs) associated with late-onset Alzheimer’s disease (LOAD) have been identified by genome-wide association studies
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and MRI markers were significant when ApoE was included in the score. Conclusions: In the Memento cohort, several non-Apoe genes are associated with neurodegenerative and vascular brain pathology. Understanding the mechanisms underlying the association of these genes with risk for disease could provide new insights on the natural history of AD.
P2-079
ASSESSMENT OF THE KNOWN AND CANDIDATE ALZHEIMER’S DISEASE GENES IN AFRICANAMERICANS
Aurelie Nsongo, Minerva M. Carrasquillo, Xue Wang, Jeremy D. Burgess, Thuy Nguyen, Yan W. Asmann, Steven G. Younkin, Neill R. Graff-Radford, Nilufer Ertekin-Taner, Mayo Clinic, Jacksonville, FL, USA. Contact e-mail: [email protected] Background: African-Americans (AAs) are approximately twice as likely to develop Alzheimer’s disease (AD) compared to Caucasians. However, little is known regarding the genetics of AD in this population. Genome wide association studies of AA subjects (GWAS) suggest that AD risk variants in this population are different from those for Caucasians; underlining the importance of expanding genetic studies of AD in the AA population. Moreover, to date no mutations in the APP, PSEN1 or PSEN2 genes were reported in AA AD subjects. Methods: Whole exome sequencing was performed on genomic DNA samples from 238 self-reported AA individuals recruited from the Mayo Clinic in Jacksonville Florida, including 131 individuals with a clinical diagnosis of AD and 107 cognitively normal controls. Allelic distributions were compared between the ADs and the controls using a Fisher’s exact test as well as logistic regression analysis adjusted for sex, age and APOE ε4 dosage. Results: Out of the 110,373 variants that remained after quality control, 206 were in genes previously associated with late onset AD risk in Caucasians (CASS4, FERMT2, HLA-DRB1, INPP5D, MEF2C, NME8, PTK2B, SLC24A4, SORL1, CELF1, ZCWPW1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, ABCA7, CD33, DSG2), among which 7 showed a nominally significant association with AD risk by logistic regression analysis (p-value < 0.05) and 3 showed a nominally significant association with AD risk by Fisher’s exact test (p-value < 0.05). In addition, 14 variants were in early-onset familial AD genes (APP, PSEN1, PSEN2), out of which, 6 were observed in at least one of our AD cases but never in our controls. Although residing in genes previously associated with/causative of AD in Caucasians, those specific variants have never been associated with AD risk in Caucasian studies. Conclusions: These preliminary results suggest that, while same genes and pathways may underlie the disease mechanism in both ethnic groups, different genetic variants may modulate the disease risk in AAs in comparison to Caucasians. Validation of these results in a larger AA cohort is currently underway.
P2-080
ASSOCIATION STUDY OF HIGH-RISK GENETIC VARIANTS WITH ALZHEIMER’S DISEASE IN THE KOREAN ELDERLY
Ji Su Lee1,2, Na Hyeon Kim1,2, Tamil Iniyan Gunasekaran1, Sa Rang Kang1,2, Wooje Lee1, Jang Jae Lee1, Kyu Yeong Choi1,3, Kun Ho Lee1,2,4, 1National Research Center for Dementia, Chosun
P640
Poster Presentations: Monday, July 25, 2016
University, Gwangju, Republic of Korea; 2Department of Life Science, Chosun University, Gwangju, Republic of Korea; 3Department of Premedics, Chosun University, Gwangju, The Republic of Korea; 4College of Natural Sciences, Chosun University, Gwangju, Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common form
of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Genome wide association studies (GWAS) in which hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested for association with a disease in hundreds or thousands of persons. Although there are several kinds of GWAS studies for AD with the Caucasian population, the studies for Asians, in particular Koreans are not sufficient. In this study, we identified several high-risk single nucleotide polymorphisms (SNPs) associated with AD in Korean population. Methods: The study consisted of 211 normal subjects and 357 AD patients from the Korean population. The two groups were further divided as 137 male and 220 female in the control group and 87 male and 124 female in the AD group respectively. The individuals aged above 50 were included to check the association with LOAD. Blood samples collected from those groups were SNP genotyped. Results: The highly AD-associated SNPs were rs4848905 (CNTNAP5) and rs75605691 (VPS13A-AS1). In addition, we performed the correlation analysis between these AD high-risk SNPs and the neuropsychological test scores in normal control group. Surprisingly, these two SNPs (rs4848905 and rs75605691) showed the strong correlations with COWAT neuropsychological assessments. Conclusions: These results suggest that the AD-risk genetic factors may cause the cognitive changes in the normal state. Taken together, the genetic variants identified in this study can serve as the potential diagnostic markers in the early diagnosis of Alzheimer’s disease.
P2-081
ASSOCIATION STUDY OF SORL1 GENE SNP RS1133174 WITH THE RISK OF AMNESTIC MILD COGNITIVE IMPAIRMENT
Chunhui Jin, Xiaowei Liu, Feng Zhang, Jianzhong Zhu, Zaohuo Cheng, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China. Contact e-mail: [email protected] Background: To explore the association of sortilin-related receptor 1 (SORL1) gene single nucleotide polymorphism (SNP) rs1133174 with the risk of amnestic mild cognitive impairment (aMCI) in the Han Chinese population. Methods: We recruited 63 aMCI patients and 179 healthy controls and genotyped the SORL1 gene SNP rs1133174 using LDR-PCR method. The association between rs1133174 and the risk of aMCI was then analyzed. Results: We found that the ‘G’ allele frequency in aMCI patients was significantly higher than that in healthy controls (OR ¼ 2.221, 95% CI ¼ 1.396-3.533, P ¼ 0.0006). A logistic regression analysis further identified that the ‘G’ allele carriers had an increased risk compared with non-carriers (GG + GA vs. AA, OR ¼2.713, 95% CI ¼ 1.4954.918, P ¼ 0.0005). Furthermore, a stratified analysis indicated that the SORL1 SNP rs1133174 might be an APOE 34-independent risk factor. Conclusions: The SORL1 gene SNP rs1133174 may be significantly associated with the risk of aMCI in the Han Chinese population.
P2-082
COMPARISON OF GENE-BASED METHODS TO IDENTIFY NOVEL ALZHEIMER’S DISEASE– ASSOCIATED GENES
Emily Ann Baker1, Valentina Escott-Price1, Rebecca Sims1, Peter Holmans1, Julie Williams1 GERAD, IGAP, 1MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Contact e-mail: [email protected] Background: Gene-based analysis may enable the determination of
novel loci associated with AD compared to single SNP analysis, since the combined effect of SNPs within genes may be captured. A novel method using polygenic risk score (PRS) is considered; this informs the analysis with previously reported effect sizes of a SNPs association to AD. Methods: GERAD data (3332 cases, 9832 controls) was used to calculate PRSs and ADGC, EADI and CHARGE data (5240 cases, 1800 controls) was used to determine effect sizes for linkage disequilibrium (LD) pruned SNPs. SNPs common to both datasets were annotated to genes. The PRS was calculated per subject per gene. Logistic regression models determined the association of the PRSgenebased for each gene with AD, accounting for population covariates. These results were compared to those produced using Fisher’s and Simes’ methods for combining p-values and the power of these methods to detect genes associated with AD were compared. We also investigated the power of our approach compared to Simes. Results: Our approach replicates the results of [1]. No novel genes have been determined, but since data was pruned, the power for the analysis to detect associated genes will likely be reduced. The PRSgenebased p-values were correlated with both Fisher’s and Simes’ p-values, with correlation strength increasing for more significant genes. Since larger genes may harbour more significant SNPs by chance, we determined the correlation between the number of SNPs per gene and the significance of a gene. There was no evidence of a significant correlation between PRSgenebased and the number of SNPs per gene (r¼-0.0054). Conclusions: In this study we applied a genebased PRS approach to LD pruned SNPs. This method will be extended for unpruned data with appropriate adjustment for LD between SNPs, thus increasing power and improving the possibility of detecting novel genes associated with AD. This method has potential to discover data-driven pathways, it may be used for prioritisation of subjects for follow-up studies (e.g. clinical trials) based upon single gene or pathway PRS, and for prioritising genes for further functional studies (e.g. animal models). [1] V.Escott-Price,C.Bellenguez,L.S.Wang,S.H.Choi,et al.,’Gene-wide analysis detects two new susceptibility genes for Alzheimer’s disease. PLoS One, vol.9,no.6,p.e94661,2014.
P2-083
COMPUTATIONAL IDENTIFICATION OF REGULATORY MECHANISMS AFFECTED BY NONCODING VARIANTS ASSOCIATED WITH LATE-ONSET ALZHEIMER’S DISEASE
Alexandre Amlie-Wolf1, Mitchell Tang1, Jessica King1, Beth A. Dombroski1, Li-San Wang2, Gerard D. Schellenberg2, 1University of Pennsylvania, Philadelphia, PA, USA; 2University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Contact e-mail: [email protected] Background: More than 20 single nucleotide polymorphisms
(SNPs) associated with late-onset Alzheimer’s disease (LOAD) have been identified by genome-wide association studies