- Email: [email protected]
Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease
P150
Oral O4-01: Genetics
assessed at UBCH-CARD, five of whom have been assessed longitudinally up to 10 years. Clinical information was also available on six deceased individuals who were reportedly affected and this was compatible with typical AD. The age of onset ranges from 55 to 66-years-old with a median age of 59 years. There is no neuropathology available to date. Allelic missense mutations (L250 V) and (L250S) have been reported previously (Furuya 2003, Mehrabian 2005, Hutton 1996, Harvey 1998). None of our patients have myoclonus, a prominent feature in the other reported families with different amino acid substitutions at this codon. Conclusions: We report a novel PS1 gene mutation, the first ever reported EOFAD gene mutation in a North American aboriginal population. The neurological features of affected individuals differ from those seen in non-aboriginal individuals with other reported PS1 mutations at the same codon. O4-01-05
GENETIC VARIANTS IN 14Q CHROMOSOMAL REGION ARE ASSOCIATED WITH MEMORY IN LATE-ONSET ALZHEIMER’S DISEASE
Sandra Barral1, Joseph H. Lee1, Rong Cheng1, Christiane Reitz1, Vincent Santana1, Jennifer Williamson1, Rafael Lantigua1, Ekaterina Rogaeva2, P. St. George Hyslop2, Richard Mayeux1, 1G.H Sergievsky Center. Columbia University, NYC, NY, USA; 2Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada. Contact e-mail: [email protected] Background: Mutations in PSEN1 (14q22), PSEN2 and APP genes are known to cause Early Onset Alzheimer’s disease. Some independent studies of late onset form (LOAD) have reported support for linkage and association of 14q region, suggesting that the 14q region may harbor additional genetic modulators of LOAD susceptibility. To circumvent the possibility that the effect of a potential risk modulating gene may be moderate, we examined the relation between SNPs and memory performance as endophenotype to enhance our statistical power. Methods: We have conducted a dense SNP mapping of the chromosomal region 14q in a large population-based sample of 1094 subjects (549 LOAD cases and 545 controls) using total recall and delayed recognition as quantitative traits to identify LOAD genetic risk factors. We additionally carried out microarray gene expression analysis in amygdala tissue from LOAD cases (N ¼ 5) and controls subjects (N ¼ 5). Results: Our results from a linear regression model after adjusting for population stratification and covariates showed nominally significant association of SNP marker rs214280, located 2 kb upstream of PSEN locus, with total recall (p ¼ 0.012) and delayed recognition (p ¼ 0.038). When further investigating linkage disequilibrium pattern, the reported SNP showed strong LD with three neighboring markers, being the subsequent haplotype strongly associated with total recall (p ¼ 8E-03). Moreover, we found additional and stronger association signals outside the 14q PSEN1 region. Specifically, SNP markers in regions 14q11, 14q23.1, 14q24.1 and 14q32 appeared significant associated with both memory traits in single marker and haplotype association tests. SNP rs2331490 in 14q11 appeared significant associated in the single marker test, with the smallest p-value ¼ 4E-05, and also significant in the haplotype test (p ¼ 1E-03). When brain expression was assessed, matrix metallopeptidase gene, MMP14, located 718Kb downstream the associated SNP, showed significantly lower expression of in AD brains compared to control brains (p ¼ 0.008). Experimental studies have suggested that matrix metalloproteinase are involved in the degradation of amyloid beta protein. Genetic variants modulating MMP activity might have the potential to influence Amyloid beta processing in the brain and therefore play a role in AD pathogenesis. Conclusions: SNP markers located in 14q chromosomal region are associated with memory performance in LOAD. O4-01-06
GENETIC VARIATION IN PCDH11X IS ASSOCIATED WITH SUSCEPTIBILITY TO LATEONSET ALZHEIMER’S DISEASE
Minerva M. Carrasquillo1, Fanggeng Zou1, V. Shane Pankratz2, Samantha L. Wilcox1, Li Ma1, Louise P. Walker1, Samuel G. Younkin1, Curtis S. Younkin1, Linda H. Younkin1, Gina D. Bisceglio1,
Nilufer Ertekin-Taner1, Julia E. Crook1, Dennis W. Dickson1, Ronald C. Petersen2, Neill R. Graff-Radford1, Steven G. Younkin1 1 Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: We found strong association between LOAD and PCDH11X which belongs to the protocadherin gene subfamily of the cadherin superfamily of cell surface receptor molecules. Cadherins mediate cell-cell adhesion and have a role in cell signaling that is critical in the development of the central nervous system. Expression is particularly strong in the cortex and hippocampus and weaker in the cerebellum. Notably, some protocadherins undergo presenilin-dependent processing. Methods: We analyzed late-onset Alzheimer’s disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases/1,255 controls) and then evaluated the 25 SNPs with the most significant allelic association in four additional series (1,547 cases/1,209 controls). Results: One SNP (rs5984894), located in a 102-kb linkage disequilibrium (LD) block entirely within PCDH11X, was strongly associated with LOAD. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global Pvalues of 5.7 3 105 in stage 1, 4.8 3 106 in stage 2 and 3.9 3 1012 in the combined data. Odds ratios were 1.75 (95% CI ¼ 1.42-2.16) for female homozygotes (P ¼ 2.0 3 107) and 1.26 (1.05-1.51) for female heterozygotes (P ¼ 0.01) compared to female non-carriers. For male hemizygotes (P ¼ 0.07) compared to male non-carriers, the odds ratio was 1.18 (0.99-1.41). Three additional PCDH11X SNPs (rs2573905, rs5941047 and rs4568761) on the same haplotype block as rs5984894 that were subsequently analyzed in all stage 1 þ 2 subjects also showed significant association. rs2573905 is in strong LD with rs5984894 (r2 ¼ 0.98, D0 ¼ 0.99) and also showed highly significant association (global P ¼ 5.4 3 1013) when analyzed by multivariable logistic regression adjusted for sex. rs2573905 is in a 100-bp region that is 70% conserved in human/mouse sequence, so it may account for the strong association of rs5984894 with LOAD. In our combined series, women homozygous for both APOE e4 and rs2573905 comprised 4.9% of AD (75/1518) and 0.14% (2/1378) of unaffected women, an OR of 35.8. (8.8-145.9) vs 19.2 (10.7-34.5) for 4/4 alone. The two doubly homozygous unaffected women were 73, and 0/999 above 73 were doubly homozygous. Conclusions: These data suggest that double homozygosity for APOE e4 and rs2573905 may be a highly penetrant combination by age 73 that could explain w5% of LOAD in women, but more subjects must be analyzed to reach a precise conclusion. O4-01-07
GENOME-WIDE ASSOCIATION STUDY VALIDATES ASSOCIATIONS IN APOE, VDR, SORL1, WWC1, AND ELAVL4 AND IDENTIFIES NOVEL CANDIDATE GENES FOR LATE-ONSET ALZHEIMER’S DISEASE
Adam C. Naj1, Gary W. Beecham1, Michael A. Slifer1, Eden R. Martin1, Paul J. Gallins1, Ioanna Konidari1, Patrice L. Whitehead1, Guiqing Cai2, Yuji Kajiwara2, Vahram Haroutunian2, Harry E. Gwirtsman3, John R. Gilbert1, Jonathan L. Haines4, Joseph D. Buxbaum2, Margaret A. Pericak-Vance1, 1Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA; 3VA Medical Center, Nashville, TN, USA; 4Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA. Contact e-mail: anaj@ med.miami.edu Background: APOE is the only confirmed genetic risk factor for Late-onset Alzheimer disease (LOAD), accounting for 50% of the total AD genetic effect. Variants at other loci have demonstrated suggestive associations, but these signals have not been consistently validated. Genome Wide Association Studies (GWAS) are powerful for detecting small effects and are now the standard for gene mapping in complex diseases such as LOAD. The present study follows up our previously reported GWAS, providing a replication data set for our previous analyses. Methods: We used a set of 399 LOAD cases (276 autopsy-confirmed and 123 clinically-confirmed) and 356 cognitive controls (73 autopsy-confirmed and 283 clinically-confirmed) to
Oral O4-01: Genetics
assessed at UBCH-CARD, five of whom have been assessed longitudinally up to 10 years. Clinical information was also available on six deceased individuals who were reportedly affected and this was compatible with typical AD. The age of onset ranges from 55 to 66-years-old with a median age of 59 years. There is no neuropathology available to date. Allelic missense mutations (L250 V) and (L250S) have been reported previously (Furuya 2003, Mehrabian 2005, Hutton 1996, Harvey 1998). None of our patients have myoclonus, a prominent feature in the other reported families with different amino acid substitutions at this codon. Conclusions: We report a novel PS1 gene mutation, the first ever reported EOFAD gene mutation in a North American aboriginal population. The neurological features of affected individuals differ from those seen in non-aboriginal individuals with other reported PS1 mutations at the same codon. O4-01-05
GENETIC VARIANTS IN 14Q CHROMOSOMAL REGION ARE ASSOCIATED WITH MEMORY IN LATE-ONSET ALZHEIMER’S DISEASE
Sandra Barral1, Joseph H. Lee1, Rong Cheng1, Christiane Reitz1, Vincent Santana1, Jennifer Williamson1, Rafael Lantigua1, Ekaterina Rogaeva2, P. St. George Hyslop2, Richard Mayeux1, 1G.H Sergievsky Center. Columbia University, NYC, NY, USA; 2Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada. Contact e-mail: [email protected] Background: Mutations in PSEN1 (14q22), PSEN2 and APP genes are known to cause Early Onset Alzheimer’s disease. Some independent studies of late onset form (LOAD) have reported support for linkage and association of 14q region, suggesting that the 14q region may harbor additional genetic modulators of LOAD susceptibility. To circumvent the possibility that the effect of a potential risk modulating gene may be moderate, we examined the relation between SNPs and memory performance as endophenotype to enhance our statistical power. Methods: We have conducted a dense SNP mapping of the chromosomal region 14q in a large population-based sample of 1094 subjects (549 LOAD cases and 545 controls) using total recall and delayed recognition as quantitative traits to identify LOAD genetic risk factors. We additionally carried out microarray gene expression analysis in amygdala tissue from LOAD cases (N ¼ 5) and controls subjects (N ¼ 5). Results: Our results from a linear regression model after adjusting for population stratification and covariates showed nominally significant association of SNP marker rs214280, located 2 kb upstream of PSEN locus, with total recall (p ¼ 0.012) and delayed recognition (p ¼ 0.038). When further investigating linkage disequilibrium pattern, the reported SNP showed strong LD with three neighboring markers, being the subsequent haplotype strongly associated with total recall (p ¼ 8E-03). Moreover, we found additional and stronger association signals outside the 14q PSEN1 region. Specifically, SNP markers in regions 14q11, 14q23.1, 14q24.1 and 14q32 appeared significant associated with both memory traits in single marker and haplotype association tests. SNP rs2331490 in 14q11 appeared significant associated in the single marker test, with the smallest p-value ¼ 4E-05, and also significant in the haplotype test (p ¼ 1E-03). When brain expression was assessed, matrix metallopeptidase gene, MMP14, located 718Kb downstream the associated SNP, showed significantly lower expression of in AD brains compared to control brains (p ¼ 0.008). Experimental studies have suggested that matrix metalloproteinase are involved in the degradation of amyloid beta protein. Genetic variants modulating MMP activity might have the potential to influence Amyloid beta processing in the brain and therefore play a role in AD pathogenesis. Conclusions: SNP markers located in 14q chromosomal region are associated with memory performance in LOAD. O4-01-06
GENETIC VARIATION IN PCDH11X IS ASSOCIATED WITH SUSCEPTIBILITY TO LATEONSET ALZHEIMER’S DISEASE
Minerva M. Carrasquillo1, Fanggeng Zou1, V. Shane Pankratz2, Samantha L. Wilcox1, Li Ma1, Louise P. Walker1, Samuel G. Younkin1, Curtis S. Younkin1, Linda H. Younkin1, Gina D. Bisceglio1,
Nilufer Ertekin-Taner1, Julia E. Crook1, Dennis W. Dickson1, Ronald C. Petersen2, Neill R. Graff-Radford1, Steven G. Younkin1 1 Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: We found strong association between LOAD and PCDH11X which belongs to the protocadherin gene subfamily of the cadherin superfamily of cell surface receptor molecules. Cadherins mediate cell-cell adhesion and have a role in cell signaling that is critical in the development of the central nervous system. Expression is particularly strong in the cortex and hippocampus and weaker in the cerebellum. Notably, some protocadherins undergo presenilin-dependent processing. Methods: We analyzed late-onset Alzheimer’s disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases/1,255 controls) and then evaluated the 25 SNPs with the most significant allelic association in four additional series (1,547 cases/1,209 controls). Results: One SNP (rs5984894), located in a 102-kb linkage disequilibrium (LD) block entirely within PCDH11X, was strongly associated with LOAD. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global Pvalues of 5.7 3 105 in stage 1, 4.8 3 106 in stage 2 and 3.9 3 1012 in the combined data. Odds ratios were 1.75 (95% CI ¼ 1.42-2.16) for female homozygotes (P ¼ 2.0 3 107) and 1.26 (1.05-1.51) for female heterozygotes (P ¼ 0.01) compared to female non-carriers. For male hemizygotes (P ¼ 0.07) compared to male non-carriers, the odds ratio was 1.18 (0.99-1.41). Three additional PCDH11X SNPs (rs2573905, rs5941047 and rs4568761) on the same haplotype block as rs5984894 that were subsequently analyzed in all stage 1 þ 2 subjects also showed significant association. rs2573905 is in strong LD with rs5984894 (r2 ¼ 0.98, D0 ¼ 0.99) and also showed highly significant association (global P ¼ 5.4 3 1013) when analyzed by multivariable logistic regression adjusted for sex. rs2573905 is in a 100-bp region that is 70% conserved in human/mouse sequence, so it may account for the strong association of rs5984894 with LOAD. In our combined series, women homozygous for both APOE e4 and rs2573905 comprised 4.9% of AD (75/1518) and 0.14% (2/1378) of unaffected women, an OR of 35.8. (8.8-145.9) vs 19.2 (10.7-34.5) for 4/4 alone. The two doubly homozygous unaffected women were 73, and 0/999 above 73 were doubly homozygous. Conclusions: These data suggest that double homozygosity for APOE e4 and rs2573905 may be a highly penetrant combination by age 73 that could explain w5% of LOAD in women, but more subjects must be analyzed to reach a precise conclusion. O4-01-07
GENOME-WIDE ASSOCIATION STUDY VALIDATES ASSOCIATIONS IN APOE, VDR, SORL1, WWC1, AND ELAVL4 AND IDENTIFIES NOVEL CANDIDATE GENES FOR LATE-ONSET ALZHEIMER’S DISEASE
Adam C. Naj1, Gary W. Beecham1, Michael A. Slifer1, Eden R. Martin1, Paul J. Gallins1, Ioanna Konidari1, Patrice L. Whitehead1, Guiqing Cai2, Yuji Kajiwara2, Vahram Haroutunian2, Harry E. Gwirtsman3, John R. Gilbert1, Jonathan L. Haines4, Joseph D. Buxbaum2, Margaret A. Pericak-Vance1, 1Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA; 3VA Medical Center, Nashville, TN, USA; 4Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA. Contact e-mail: anaj@ med.miami.edu Background: APOE is the only confirmed genetic risk factor for Late-onset Alzheimer disease (LOAD), accounting for 50% of the total AD genetic effect. Variants at other loci have demonstrated suggestive associations, but these signals have not been consistently validated. Genome Wide Association Studies (GWAS) are powerful for detecting small effects and are now the standard for gene mapping in complex diseases such as LOAD. The present study follows up our previously reported GWAS, providing a replication data set for our previous analyses. Methods: We used a set of 399 LOAD cases (276 autopsy-confirmed and 123 clinically-confirmed) and 356 cognitive controls (73 autopsy-confirmed and 283 clinically-confirmed) to