- Email: [email protected]
Genome-Wide Association Study for Alzheimer’s Disease with Psychotic Symptoms
S186
P1-234
Poster Presentations P1
PRESENILINS PROMOTE THE CELLULAR UPTAKE OF COPPER AND ZINC AND MAINTAIN CU/ZN-DEPENDENT SUPEROXIDE DISMUTASE ACTIVTITY
Mark Greenough1, Irene Volitakis2, Qiao-Xin Li1, Genevieve Evin1, Andrew Dalziel1, James Camakaris1, Ashley Bush2, 1The University of Melbourne, Melbourne, Australia; 2Mental Health Research Institute, Melbourne, Australia. Background: Dyshomeostasis of zinc and copper has been implicated in beta-amyloid aggregation, one of the major pathologies associated with Alzheimer’s disease. Presenilin mediates the proteolytic cleavage of the beta-amyloid precursor protein to release beta-amyloid and mutations in presenilin can cause familial Alzheimer’s disease. In this study we set out to determine what role, if any, presenilin could play in metal homeostasis, with particular focus on the cellular uptake of copper, zinc and iron. We also sought to establish if loss of presenilin function could adversely effect the activity of the vital Cu/Zn-dependent antioxidant enzyme, superoxide dismutase 1 (SOD1). Methods: Using presenilin knockout mice and cultured murine embryonic fibroblasts (MEFs) cells we have identified a novel role for presenilin in copper and zinc homeostasis. Results: We observed a marked decrease in saturable uptake of radiolabeled copper and zinc in presenilin knockout MEFs. Measurement of basal metal levels in six month old presenilin 1 heterozygous knockout PS1+/- mice revealed significant deficiencies of copper and zinc in several tissues, including brain. SOD1 activity was significantly decreased in both presenilin knockout MEFs and brain tissue of presenilin 1 heterozygous knockout mice. In the MEFs and PS1+/brains Cu-chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. Conclusions: These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact beta-amyloid aggregation through metal ion clearance. P1-235
TOMM40 “523” GENOTYPE AFFECTS AGE OF ALZHEIMER’S DISEASE ONSET DIFFERENTIALLY BY RACE
Kathleen Hayden, Michael Lutz, Ann Saunders, Heather Romero, James Burke, Kathleen Welsh-Bohmer, Allen Roses, Duke University Medical Center, Durham, North Carolina, United States. Background: The TOMM40 gene encodes the translocase of the outer mitochondrial membrane pore subunit, and is in linkage disequilibrium with APOE. The length of a poly-T variant ("523") within intron 6 of TOMM40 has been shown to predict the age of onset of late onset Alzheimer’s Disease (LOAD). We present new data using Kaplan Meier (KM) survival curves showing the effect of “523” on LOAD within a large, well-characterized sample followed annually for up to five years. Methods: The Bryan ADRC Memory Health and Aging study is comprised of a diverse group of residents from the local community (28% African-American; AfrAmer) all of whom were independent in their daily function at baseline. They were visited in the home or in the clinic annually and evaluated on a number of measures including a neuropsychological test battery, health history, behavioral functional assessments, and neurological evaluation. Using a sample of n ¼ 438 participants, cognitively normal at baseline, we produced empirical survival curves to estimate age-specific proportions of participants surviving for TOMM40 “523” genotypes based on poly-T length. Individuals were followed over time until death, dementia onset, including probable or possible AD, or their last visit. Results: A total of 106 individuals were diagnosed with dementia at a mean age of 78 (SD 8.0) years. KM curves show an effect (p < 0.0001, log rank test) of “523” genotype on age of LOAD onset, with age at 50% affected ranging from 75 to 94 years and a 3-5 year separation between curves. Ethnicity has an effect (p ¼ 0.004) on LOAD onset whereas gender and years of education were not statistically-significant covariates. Limiting analysis to individuals with the APOE 3 /3 genotype (n ¼ 199) showed a significant effect (p < 0.02) of “523” on LOAD onset. Conclusions: “523” genotypes define characteristic age of onset curves for LOAD which provide additional temporal resolution
to curves based on APOE genotype. Results suggest that the age of onset in AfrAmer in this cohort is earlier, across all “523” genotypes, however this needs to be studied further as there were few AfrAmer in the sample. P1-236
GENOME-WIDE ASSOCIATION STUDY FOR ALZHEIMER’S DISEASE WITH PSYCHOTIC SYMPTOMS
Paul Hollingworth1, Robert Sweet2, Rebecca Sims1, Denise Harold1, Richard Abraham1, Amy Gerrish1, Bernie Devlin2, Lambertus Klei2, Michael Barmada3, Yesim Demirci2, Steven DeKosky2, Oscar Lopez2, Peter Passmore4, Richard Mayeux5, Ilyas Kamboh2, Julie Williams6, 1 Cardiff University, Cardiff, United Kingdom; 2University of Pittsburgh, Pittsburgh, Pennsylvania, United States; 3Columbia University, New York, New York, United Kingdom; 4Queen’s University of Belfast, Belfast, United Kingdom; 5Columbia University, New York, New York, United States; 6 1 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom. Background: Alzheimer’sdisease (AD) is genetically complex. Recent genome-wide association studies (GWAS) have reported compelling evidence for several novel AD risk loci. However, a substantial proportion of heritability remains unexplained. Psychotic symptoms occur in approximately 40% of those with AD and are associated with more rapid disease progression, increased functional deficits and earlier institutionalization. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. Here we report the largest GWAS for psychotic symptoms reported to date. Methods: We undertook a meta-analysis of available GWAS data from three independent samples, comprising 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls. Samples were drawn from GERAD1, the University of Pittsburgh AD Research Center, and the National Institute on Aging’s Genetics Initiative for Late-onset AD Family Study. Psychotic symptoms were assessed using the Neuropsychiatric Inventory, NPI-Q or CERAD behavioural rating scale. Samples were genotyping using either the Illumina 610 or Omni1-Quad chip. Unobserved genotypes were imputed in the GERAD1 and ADRC samples to increase SNP overlap between studies. Analyses in each dataset were completed comparing AD+Pcases to a) AD-P cases, and b) controls. Summary statistics were combined using inverse variance weighted meta-analysis. Results: When comparing AD cases with and without psychosis, 40 independent (r2 > 0.2) associations with P < 1x104 were identified, 8 of which had P < 1x105. The strongest evidence for association was observed in an intergenic region on chromosome 4 (AD+PvAD-P P ¼ 2.85x 107; AD+PvControl P ¼ 1.11 x 104). For AD+P compared to controls, 42 novel independent loci were identified which showed association at the P < ;1x104 level with AD+P, but were not associated with AD alone, irrespective of psychosis status (P > 0.01). The most significant SNP was located on chromosome 2 (AD+Pv Control P ¼ 5.9x107; AD+PvAD-P P ¼ 1.84x102). Conclusions: Previous evidence suggests that psychotic symptoms may characterise a distinct and more severe disease subtype. Identification of genetic variation associated with AD+P will further our understanding of the disease mechanisms that underlie behavioural features of AD and will have implications for other complex genetic disorders where psychotic symptoms are common. P1-237
GENOME-WIDE ASSOCIATION STUDY OF EXECUTIVE FUNCTION
Carla Ibrahim-Verbaas1, Stephanie Debette2, Jan Bressler3, Maaike Schuur1, Albert Vernon Smith4, Josh Bis5, Gail Davies6, Katja Petrovic7, Mirna Kirin6, Lina Zgaga6, Caroline Hayward8, Qiong Yang9, Helena Schmidt7, Monique Breteler1, James Wilson6, Sudha Seshadri2, Reinhold Schmidt7, Annette Fitzpatrick5, Ian Deary6, Cornelia van Duijn1, Mohammad Ikram10, Lenore Launer11, Thomas Mosley12, 1Erasmus University Medical Center, Rotterdam, Netherlands; 2Boston University School of Medicine, Boston, Massachusetts, United States; 3University of Texas School of Public Health, Houston, Texas, United States; 4Icelandic Heart Association, Kopavogur, Iceland; 5University of Washington, Seattle, Washington, United States;
P1-234
Poster Presentations P1
PRESENILINS PROMOTE THE CELLULAR UPTAKE OF COPPER AND ZINC AND MAINTAIN CU/ZN-DEPENDENT SUPEROXIDE DISMUTASE ACTIVTITY
Mark Greenough1, Irene Volitakis2, Qiao-Xin Li1, Genevieve Evin1, Andrew Dalziel1, James Camakaris1, Ashley Bush2, 1The University of Melbourne, Melbourne, Australia; 2Mental Health Research Institute, Melbourne, Australia. Background: Dyshomeostasis of zinc and copper has been implicated in beta-amyloid aggregation, one of the major pathologies associated with Alzheimer’s disease. Presenilin mediates the proteolytic cleavage of the beta-amyloid precursor protein to release beta-amyloid and mutations in presenilin can cause familial Alzheimer’s disease. In this study we set out to determine what role, if any, presenilin could play in metal homeostasis, with particular focus on the cellular uptake of copper, zinc and iron. We also sought to establish if loss of presenilin function could adversely effect the activity of the vital Cu/Zn-dependent antioxidant enzyme, superoxide dismutase 1 (SOD1). Methods: Using presenilin knockout mice and cultured murine embryonic fibroblasts (MEFs) cells we have identified a novel role for presenilin in copper and zinc homeostasis. Results: We observed a marked decrease in saturable uptake of radiolabeled copper and zinc in presenilin knockout MEFs. Measurement of basal metal levels in six month old presenilin 1 heterozygous knockout PS1+/- mice revealed significant deficiencies of copper and zinc in several tissues, including brain. SOD1 activity was significantly decreased in both presenilin knockout MEFs and brain tissue of presenilin 1 heterozygous knockout mice. In the MEFs and PS1+/brains Cu-chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. Conclusions: These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact beta-amyloid aggregation through metal ion clearance. P1-235
TOMM40 “523” GENOTYPE AFFECTS AGE OF ALZHEIMER’S DISEASE ONSET DIFFERENTIALLY BY RACE
Kathleen Hayden, Michael Lutz, Ann Saunders, Heather Romero, James Burke, Kathleen Welsh-Bohmer, Allen Roses, Duke University Medical Center, Durham, North Carolina, United States. Background: The TOMM40 gene encodes the translocase of the outer mitochondrial membrane pore subunit, and is in linkage disequilibrium with APOE. The length of a poly-T variant ("523") within intron 6 of TOMM40 has been shown to predict the age of onset of late onset Alzheimer’s Disease (LOAD). We present new data using Kaplan Meier (KM) survival curves showing the effect of “523” on LOAD within a large, well-characterized sample followed annually for up to five years. Methods: The Bryan ADRC Memory Health and Aging study is comprised of a diverse group of residents from the local community (28% African-American; AfrAmer) all of whom were independent in their daily function at baseline. They were visited in the home or in the clinic annually and evaluated on a number of measures including a neuropsychological test battery, health history, behavioral functional assessments, and neurological evaluation. Using a sample of n ¼ 438 participants, cognitively normal at baseline, we produced empirical survival curves to estimate age-specific proportions of participants surviving for TOMM40 “523” genotypes based on poly-T length. Individuals were followed over time until death, dementia onset, including probable or possible AD, or their last visit. Results: A total of 106 individuals were diagnosed with dementia at a mean age of 78 (SD 8.0) years. KM curves show an effect (p < 0.0001, log rank test) of “523” genotype on age of LOAD onset, with age at 50% affected ranging from 75 to 94 years and a 3-5 year separation between curves. Ethnicity has an effect (p ¼ 0.004) on LOAD onset whereas gender and years of education were not statistically-significant covariates. Limiting analysis to individuals with the APOE 3 /3 genotype (n ¼ 199) showed a significant effect (p < 0.02) of “523” on LOAD onset. Conclusions: “523” genotypes define characteristic age of onset curves for LOAD which provide additional temporal resolution
to curves based on APOE genotype. Results suggest that the age of onset in AfrAmer in this cohort is earlier, across all “523” genotypes, however this needs to be studied further as there were few AfrAmer in the sample. P1-236
GENOME-WIDE ASSOCIATION STUDY FOR ALZHEIMER’S DISEASE WITH PSYCHOTIC SYMPTOMS
Paul Hollingworth1, Robert Sweet2, Rebecca Sims1, Denise Harold1, Richard Abraham1, Amy Gerrish1, Bernie Devlin2, Lambertus Klei2, Michael Barmada3, Yesim Demirci2, Steven DeKosky2, Oscar Lopez2, Peter Passmore4, Richard Mayeux5, Ilyas Kamboh2, Julie Williams6, 1 Cardiff University, Cardiff, United Kingdom; 2University of Pittsburgh, Pittsburgh, Pennsylvania, United States; 3Columbia University, New York, New York, United Kingdom; 4Queen’s University of Belfast, Belfast, United Kingdom; 5Columbia University, New York, New York, United States; 6 1 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom. Background: Alzheimer’sdisease (AD) is genetically complex. Recent genome-wide association studies (GWAS) have reported compelling evidence for several novel AD risk loci. However, a substantial proportion of heritability remains unexplained. Psychotic symptoms occur in approximately 40% of those with AD and are associated with more rapid disease progression, increased functional deficits and earlier institutionalization. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. Here we report the largest GWAS for psychotic symptoms reported to date. Methods: We undertook a meta-analysis of available GWAS data from three independent samples, comprising 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls. Samples were drawn from GERAD1, the University of Pittsburgh AD Research Center, and the National Institute on Aging’s Genetics Initiative for Late-onset AD Family Study. Psychotic symptoms were assessed using the Neuropsychiatric Inventory, NPI-Q or CERAD behavioural rating scale. Samples were genotyping using either the Illumina 610 or Omni1-Quad chip. Unobserved genotypes were imputed in the GERAD1 and ADRC samples to increase SNP overlap between studies. Analyses in each dataset were completed comparing AD+Pcases to a) AD-P cases, and b) controls. Summary statistics were combined using inverse variance weighted meta-analysis. Results: When comparing AD cases with and without psychosis, 40 independent (r2 > 0.2) associations with P < 1x104 were identified, 8 of which had P < 1x105. The strongest evidence for association was observed in an intergenic region on chromosome 4 (AD+PvAD-P P ¼ 2.85x 107; AD+PvControl P ¼ 1.11 x 104). For AD+P compared to controls, 42 novel independent loci were identified which showed association at the P < ;1x104 level with AD+P, but were not associated with AD alone, irrespective of psychosis status (P > 0.01). The most significant SNP was located on chromosome 2 (AD+Pv Control P ¼ 5.9x107; AD+PvAD-P P ¼ 1.84x102). Conclusions: Previous evidence suggests that psychotic symptoms may characterise a distinct and more severe disease subtype. Identification of genetic variation associated with AD+P will further our understanding of the disease mechanisms that underlie behavioural features of AD and will have implications for other complex genetic disorders where psychotic symptoms are common. P1-237
GENOME-WIDE ASSOCIATION STUDY OF EXECUTIVE FUNCTION
Carla Ibrahim-Verbaas1, Stephanie Debette2, Jan Bressler3, Maaike Schuur1, Albert Vernon Smith4, Josh Bis5, Gail Davies6, Katja Petrovic7, Mirna Kirin6, Lina Zgaga6, Caroline Hayward8, Qiong Yang9, Helena Schmidt7, Monique Breteler1, James Wilson6, Sudha Seshadri2, Reinhold Schmidt7, Annette Fitzpatrick5, Ian Deary6, Cornelia van Duijn1, Mohammad Ikram10, Lenore Launer11, Thomas Mosley12, 1Erasmus University Medical Center, Rotterdam, Netherlands; 2Boston University School of Medicine, Boston, Massachusetts, United States; 3University of Texas School of Public Health, Houston, Texas, United States; 4Icelandic Heart Association, Kopavogur, Iceland; 5University of Washington, Seattle, Washington, United States;