Association Study of Late-Onset

Slides:

Advertisements

Similar presentations

EPIDEMIOLOGY AND GENETICS OF ALZHEIMER´S DISEASE

Advertisements

Genetic Variants Associated with Late-Onset Alzheimer Disease By: Sarah Hinton, University of Georgia 2014 Pharm.D. candidate Preceptor: Dr. Ali Rahimi.

Supported by grants from: National Human Genome Research Institute (ELSI) HG/AG (The REVEAL Study); National Institute on Aging AG (The MIRAGE.

The association between blood pressure, body composition and birth weight of rural South African children: Ellisras longitudinal study Makinta MJ 1, Monyeki.

Delay from Testing HIV Positive until First HIV Care for Drug Users: Adverse Consequences and Possible Solutions Barbara J Turner MD, MSEd* John Fleishman.

Is low-dose Aspirin use associated with a reduced risk of colorectal cancer ? a QResearch primary care database analysis Prof Richard Logan, Dr Yana Vinogradova,

1 FSTL4 and SEMA5A are associated with alcohol dependence: meta- analysis of two genome-wide association studies Kesheng Wang, PhD Department of Biostatistics.

“Does African ancestry protect against dementia? A population-based case-control study in an admixed Cuban population?. ” Juan J. Llibre Rodriguez, Beatriz.

Mild Cognitive Impairment as a Target for Drug Development Steven H. Ferris, Ph.D. Silberstein Aging and Dementia Research Center New York University School.

Design Considerations in Large- Scale Genetic Association Studies Michael Boehnke, Andrew Skol, Laura Scott, Cristen Willer, Gonçalo Abecasis, Anne Jackson,

Supplementary Table 1 Table S1. Population frequency of HLA -A, -B and -C alleles. Rare alleles (frequency < 0.5%) are highlighted by a grey background.

Association study of 5-HT2A genes with schizophrenia in the Malaysian population: A Multiethnic Meta- analysis Study Shiau Foon Tee* 1, Tze Jen Chow 1,

Chapter 25 Chapter 25 Genetic Determinants of Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved.

Figure S1. Quantile-quantile plot in –log10 scale for the individual studies The red line represents concordance of observed and expected values. The shaded.

Generously supported by the Robert Wood Johnson Foundation Clinical Scholars Program, Department of Veteran Affairs, and National Institutes of Health,

Two RANTES gene polymorphisms and their haplotypes in patients with myocardial infarction from two Slavonic populations Two RANTES gene polymorphisms and.

Lipoatrophy and lipohypertrophy are independently associated with hypertension: the effect of lipoatrophy but not lipohypertrophy on hypertension is independent.

Prevalence of Dry Eye Disease among Elderly Korean Population Sang Beom Han, MD, 1 Joon Young Hyon, MD, 1 Won Ryang Wee, MD, 2,3 Jin Hak Lee, MD, 1, 3.

Organization of statistical research. The role of Biostatisticians Biostatisticians play essential roles in designing studies, analyzing data and.

BIOSTATISTICS Lecture 2. The role of Biostatisticians Biostatisticians play essential roles in designing studies, analyzing data and creating methods.

PHQ-9 Severity and Screening Tests Predictive of Remission Outcomes at Six Months Kurt B. Angstman, MS MD Associate Professor John M. Wilkinson Assistant.

 2012 Mayo Foundation for Medical Education and Research Investigation of established AD risk SNPs for association with AD in an African American Case.

Association Study of Late-Onset Alzheimer's Disease Risk Variants and Risk for Posterior Cortical Atrophy Minerva M. Carrasquillo 1, Qurat ul Ain Khan.

 2014 Mayo Foundation for Medical Education and Research Transcript profiling analysis of Alzheimer’s disease brains Mariet Allen 1, Daniel Serie 4, Michael.

 2011 Mayo Foundation for Medical Education and Research Novel late-onset Alzheimer’s disease loci variants associate with brain gene expression Mariet.

EBF FLJ31951UBLCP1 IL12B B36 Position Genes LD Regions Genotyped Markers Chr5 (q33.3) rs rs Figure 1. Physical map of 360kb around IL12B.

DIABETES AS A RISK FACTOR FOR COGNITIVE DECLINE IN OLDER PATIENTS F. Limongi, A. Marseglia, S. Maggi, M. Noale, G. Romanato, P. Siviero, G. Crepaldi CNR,

 2013 Mayo Foundation for Medical Education and Research MAPT haplotypes associate with Alzheimer's disease risk and brain gene expression Mariet Allen.

Genetic Susceptibility Variations and Visual Field Progression in Singaporean Chinese Patients with Primary Angle Closure Glaucoma 1 Duke-National University.

Date of download: 9/20/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Effects of a Palliative Care Intervention on Clinical.

Date of download: 11/12/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Influence of Child Abuse on Adult DepressionModeration.

Hearing Aid Use and Perceived Hearing Handicap in Older Adults

1University of Kentucky, Lexington, Kentucky

Bilingualism or multilingualism has protective effect on dementia onset: is there any evidence? A systematic review Yadav AK, Yadav J, Kumar P, Sagar R,

Peng Yin1, Andrea L Jorgensen1, Andrew P Morris1, Richard Turner2, Richard Fitzgerald2, Rod Stables3, Anita Hanson2, Munir Pirmohamed2 1. Department of.

Applications to AD with Sample SAS Codes

colorectal cancer: The Multiethnic Cohort

Figure 1. Onset of PIV catheter complications

Wechsler Test-Retest Combinations

Copyright © 2000 American Medical Association. All rights reserved.

Inflammatory Bowel Disease (IBD) is a Risk Factor for Extrahepatic Cholangiocarcinoma (ECC) in Subjects Without Underlying Primary Sclerosing Cholangitis.

“The Bulgarians stand at the basis of human civilization

Mayo Clinic College of Medicine

An Electronic Medical Record Based Pharmacogenetic Study

Whole Genome Methylation and MTHFR (C677T) polymorphism in Alcohol Dependence Bhagyalakshmi Shankarappa; Anirrudh Basu; Shwetha Byrappa; Rashmi Chandra;

CANDIDATE GENE STUDIES AND GWAS SUGGEST SUBSTANTIAL GENETIC INFLUENCE ON DEFICITS IN OLFACTORY IDENTIFICATION AMONG PERSONS AT RISK OF AD Marie-Elyse.

1 GENETIC POLYMORPHISMS FROM CHRONIC OBSTRUCTIVE PULMONARY DISEASE GENOME-WIDE ASSOCIATION STUDIES IN ALPHA-1 ANTITRYPSIN DEFICIENCY H Khiroya, PR Newby,

ASSOCIATIONS BETWEEN ANXA11 RS C/T, BTNL2 RS G/A, HLA CLASS I AND II POLYMORPHISMS AND SARCOIDOSIS EVOLUTION Manuel Vaz1, Bruno Lima2, Natália.

Come my friend. Let’s forget the cares of tomorrow

Gene Hunting: Design and statistics

Rare, Low-Frequency, and Common Variants in the Protein-Coding Sequence of Biological Candidate Genes from GWASs Contribute to Risk of Rheumatoid Arthritis

PPMI in the Medical Literature

From the Indianapolis – Ibadan Dementia Research Project.

Correlation for a pair of relatives

Does Multilingualism Protect Against Alzheimer’s Disease

Jae Woong Sull, Sun Ha Jee Eulji University, Yonsei University

Figure Revised Niemann-Pick disease type C (NP-C) diagnostic algorithm for the use of biomarkers and genetic testing Revised Niemann-Pick disease type.

Figure 2 Association between coronary artery disease polygenic risk score and the presence of migraine Results are given as odds ratios with 95% confidence.

Elliott P, et al. JAMA 2009;302:37-48.

Figure 2 Comparison between noncarriers (−) and carriers (+) of the minor allele of rs (CYP2C19)‏ Comparison between noncarriers (−) and carriers.

Genetic Investigations of Kidney Disease: Core Curriculum 2013

Figure 2 LocusZoom plots

Baseline Characteristics of the Subjects

Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Figure 2 Correlation between wGRS and age at onset The figure shows the correlation between weighted genetic risk score (wGRS) and age at onset in all.

Towfique Raj, Joshua M. Shulman, Brendan T. Keenan, Lori B

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort Octavio A. Santos, Otto Pedraza, John A. Lucas,

Box plot showing the distribution of the TYM-MCI score for patients with SMC and aMCI/AD. aMCI/AD, amnestic mild cognitive impairment or Alzheimer’s disease;

Public Health Implications

Amanda L. Tapia Department of Biostatistics

Presentation transcript:

Association Study of Late-Onset Alzheimer's Disease Risk Variants and Memory Decline Minerva Carrasquillo1, Julia Crook2, Otto Pedraza3, Colleen S. Thomas2, V. Shane Pankratz4, Mariet Allen1, Thuy Nguyen1, Kimberly Malphrus1, Li Ma1, Gina Bisceglio1, Rosebud Roberts5, John Lucas3, Robert Ivnik6, Mary Machulda6, Neill Graff-Radford7, Ronald Petersen8, Steven Younkin1 and Nilüfer Ertekin-Taner1,7 1Neuroscience Mayo Clinic Florida Jacksonville FL 2 Biostatistics Unit Mayo Clinic Florida Jacksonville FL 3 Department of Psychiatry and Psychology Mayo Clinic Florida Jacksonville FL 4 Depatment of Biostatistics Mayo Clinic Minnesota Rochester MN 5 Division of Epidemiology Mayo Clinic Minnesota Rochester MN 6 Department of Psychiatry and Psychology Mayo Clinic Minnesota Rochester MN 7 Department of Neurology Mayo Clinic Florida Jacksonville FL 8 Department of Neurology Mayo Clinic Minnesota Rochester MN Objective: To investigate the late-onset Alzheimer's disease (LOAD) risk variants identified from genome-wide association studies (GWAS) for their influence on human memory decline in a longitudinal series. Summary and Conclusions: APOE is associated with lower memory scores at mean age in all subjects and at first age at assessment for subjects who are cognitively normal at baseline. APOE is also associated with faster memory decline in both groups as expected. The protective CLU allele associated with better memory in both groups, but did not associate with slope of memory change. A weighted genetic risk score associated with memory at mean age or baseline, but not with slopes. This association remained significant in all subjects after controlling for the CLU genotypes, suggesting a combined effect of the remaining GWAS SNPs (or a subset thereof) on memory. Our results suggest that the use of memory endophenotypes in longitudinal series might be a viable approach in assessing the role of LOAD risk variants in human cognition. These results need to be confirmed in similar series. Table 1. Description of cohort Table 2. Description of SNPs Table 4. Association of LOAD risk SNPs with Memory SNP ID Nearest Gene Location Major Allele Minor Allele Control MAF Risk Allele OR rs11136000 CLU Intron 3 G A 0.41 1.22 rs3851179 PICALM 88.5 kb 5' 0.37 1.25 rs3818361 CR1 Intron 34 0.20 1.15 rs3764650 ABCA7 Intron 13 C 0.09 1.23 rs744373 BIN1 29.7 kb 5' 0.27 1.17 rs610932 MS4A6A 3' UTR 0.43 rs11767557 EPHA1 3.2 kb 5' 0.21 rs9349407 CD2AP Intron 1 0.29 1.11 rs3865444 CD33 373 bp 5' 0.32 1.09 Description of alleles associated with risk at the 9 LOAD GWAS risk loci. Location is relative to the nearest gene, based on the human genome assembly hg18. The minor allele frequency (MAF) and odds ratios (OR) are based on references 6-8. Weighted genetic risk score (Table 5) was calculated based on these odds ratio estimates. Scorei = 100*[Σ (nij * log(ORj)) ] / [2*Σ (log(ORj))] for the ith patient, where: nij= number of risk alleles for the ith patient and jth SNP; ORj=odds ratio for the jth SNP. Variable Summary MCR MCJ (N=2594) (N=2080) (N=514) Age at first assessment (years) 77 (49-99) 78 (55-99) 73 (49-91) Gender (male) 1160 (45%) 984 (47%) 176 (34%) Education (years) 14 (4-20) 13 (5-20) 16 (4-20) Diagnosis at first assessment Normal 1893 (73%) 1468 (71%) 425 (83%) MCI 359 (14%) 338 (16%) 21 (4%) AD 342 (13%) 274 (13%) 68 (13%) MRLMD at first assessment 16 (1-42) 15 (1-40) 19 (1-42) APOE (number of e4 alleles) 1860 (72%) 1520 (73%) 340 (67%) 1 666 (26%) 514 (25%) 152 (30%) 2 60 (2%) 45 (2%) 15 (3%) CLU-rs11136000 A A 398 (16%) 334 (17%) 64 (13%) A G 1206 (48%) 956 (48%) 250 (50%) G G 891 (36%) 706 (35%) 185 (37%) PICALM-rs3851179 332 (13%) 268 (13%) 1173 (47%) 948 (48%) 225 (45%) 984 (40%) 774 (39%) 210 (42%) CR1-rs3818361 105 (4%) 82 (4%) 23 (5%) 799 (32%) 628 (31%) 171 (34%) 1605 (64%) 1298 (65%) 307 (61%) ABCA7-rs3764650 C C 25 (1%) 20 (1%) 5 (1%) C A 379 (15%) 288 (14%) 91 (18%) 2146 (84%) 1738 (85%) 408 (81%) BIN1-rs744373 190 (8%) 137 (7%) 53 (11%) G A 987 (40%) 787 (40%) 200 (41%) 1285 (52%) 1049 (53%) 236 (48%) MS4A6A-rs610932 457 (18%) 357 (18%) 100 (20%) A C 1211 (49%) 969 (49%) 242 (49%) 825 (33%) 670 (34%) 155 (31%) EPHA1-rs11767557 113 (5%) 93 (5%) 20 (4%) 764 (31%) 604 (31%) 160 (32%) 1564 (64%) 1248 (64%) 316 (64%) CD2AP-rs9349407 185 (7%) 144 (7%) 41 (8%) C G 970 (39%) 773 (39%) 197 (40%) 1321 (53%) 1067 (54%) 254 (52%) CD33-rs3865444 237 (9%) 197 (10%) 40 (8%) 1083 (43%) 880 (44%) 203 (41%) 1182 (47%) 935 (46%) 247 (50%) Risk score 21.1 (0.0-67.2) 21.0 (0.0-67.2) 22.0 (2.3-45.1) Sample median (minimum-maximum) is given for numerical variables. MRLMD: logical memory delayed recall score (plausible range: 0 to 50). Subjects with MRLMD scores of 0 at first assessment were excluded from analyses. Genotype counts (frequencies) for the tested SNPs are shown. All Subjects Normal at Baseline Estimated change in MRLMD 95% CI pvalue Lower Upper CLU-rs11136000 (A-protective) Intercept 0.40 0.03 0.78 3.49E-02 0.51 0.11 0.92 1.28E-02 Slope 0.06 -0.03 0.14 NS 0.04 -0.05 0.13 Overall 6.34E-02 1.30E-02 PICALM-rs3851179 (A-protective) 0.00 -0.38 0.38 -0.29 -0.70 0.01 -0.08 0.09 -0.01 -0.10 0.08 CR1-rs3818361 (A-risky) 0.31 -0.14 0.77 -0.18 0.80 -0.11 0.10 0.02 -0.09 ABCA7-rs3764650 (C-risky) -1.02 0.26 -0.44 -1.15 0.27 -0.16 BIN1-rs744373 (G-risky) -0.33 0.50 0.12 0.57 -0.04 -0.13 0.05 MS4A6A-rs610932 (A-protective) 0.28 0.65 0.36 0.76 EPHA1-rs11767557 (G-protective) 0.16 -0.30 0.61 -0.45 0.53 CD2AP-rs9349407 (C-risky) -0.52 -0.32 -0.77 CD33-rs3865444 (A-protective) -0.27 0.21 -0.23 0.64 -0.06 -0.15 CLU protective allele is associated with better memory scores at mean age of all subjects and at first age at assessment of the cognitively normal subjects at baseline. Other 8 LOAD GWAS SNPs did not have significant association with memory. Background: The recent large-scale LOAD GWAS [1-5] have reported associations meeting genome-wide significance in or near 11 genes. We and others reported replication of the AD risk association with SNPs near CLU, PICALM, CR1, ABCA7, BIN1, MS4A6A, EPHA1, CD2AP, and CD33 [4, 6-8]. Here we evaluate the association of these SNPs with cognitive decline, as this approach may provide valuable information regarding their biological consequence. Table 3. Association of APOE with Memory All Subjects Normal at Baseline Estimated change in MRLMD 95% CI pvalue Lower Upper Variables Effect on Intercept APOE (# ε4 alleles) -1.19 -1.71 -0.68 5.52E-06 -0.83 -1.40 -0.26 4.43E-03 Site (MCF) 3.93 3.25 4.61 2.32E-29 1.54 0.81 2.28 4.00E-05 Mean Age -0.23 -0.27 -0.18 1.57E-23 -0.32 -0.22 4.95E-30 Male Gender -1.03 -1.55 -0.51 1.00E-04 -1.13 -1.70 -0.56 9.00E-05 Yrs. Of Education 0.50 0.42 0.59 1.37E-28 0.55 0.45 0.64 1.22E-27 AD or MCI -8.64 -9.23 -8.05 3.40E-166 NA Effect on Slope APOE (# ε4 alleles) x Year -0.40 -0.29 1.07E-12 -0.45 -0.20 1.54E-07 Site (MCF) x Year 0.70 0.56 0.84 4.21E-23 0.66 0.96 3.52E-27 Mean Age x Year -0.04 -0.05 -0.03 3.96E-15 -0.02 1.37E-07 Male Gender x Year -0.08 -0.19 0.04 1.74E-01 -0.21 1.91E-01 Yrs. Of Education x Year 0.01 -0.01 0.03 3.43E-01 3.45E-01 Effect of APOE 8.99E-15 2.19E-10 Estimated change in logical memory delayed recall (MRLMD), 95% confidence intervals (CI) and P-value results from a linear mixed model (SAS PROC MIXED) with intercept and slope as random effects. Methods: We evaluated a longitudinal series of 2,594 subjects collected at Mayo Clinic Rochester in Minnesota (MCR, n=2,080) and Mayo Clinic Jacksonville in Florida (MCJ, n=514). Of these subjects, 1,893 were cognitively normal, 359 had mild cognitive impairment (MCI) and 342 had clinical Alzheimer’s disease (AD) at baseline (Table 1). We genotyped APOE, and the top 9 LOAD GWAS risk SNPs and investigated associations with change in logical memory delayed recall scores (MRLMD) from the Wechsler Memory Scale-Revised, collected longitudinally at 2 or more time points. Linear mixed models were used with intercept and slope as random effects to assess associations adjusting for age, sex, years of education and APOE 4. Analyses were done for all subjects and those who were cognitively normal, at baseline. References: 1. Harold D et al. Nat Genet 2009, 41:1088. 2. Lambert JC et al. Nat Genet 2009, 41:1094. 3. Seshadri S et al. JAMA 2010, 303:1832. 4. Hollingworth P et al. Nat Genet 2011,43:429. 5. Naj AC et al. Nat Genet 2011,43:436. 6. Carrasquillo MM et al. Arch Neurol 2010, 67:961. 7. Carrasquillo MM et al. J Alzheimers Dis 2011, 24:751. 8. Carrasquillo MM et al. Mol Neurodegener 2011, 6:54. Table 5. Association of Risk Score with Memory All Subjects Normal at Baseline Estimated change in MRLMD 95% CI pvalue Lower Upper Basic model Intercept -0.41 -0.81 -0.01 4.65E-02 -0.56 -1.00 -0.12 1.37E-02 Slope 0.03 -0.06 0.11 NS 0.07 -0.02 0.16 Overall 9.49E-02 2.89E-02 CLU-adjusted -0.54 -1.04 -0.04 3.42E-02 -0.38 -0.92 0.17 0.01 -0.10 0.12 0.06 0.18 9.53E-02 3.03E-01 A weighted risk score calculated from OR estimates of tested SNPs (Table 2) associates with worse memory at mean age of all subjects and at first age at assessment of the cognitively normal control subjects at baseline. This association is significant in all subjects even after controlling for the CLU locus SNP. Figure 1. Longitudinal Memory Plots Acknowledgements: Supported by National Institute on Aging (R01 032990 to NET and R01 AG018023 to NRG-R and SGY); Mayo Alzheimer's Disease Research Center: (P50 AG016574 to RCP, NRG-R, SGY, and NET); GHR Foundation Award for Alzheimer's Disease Research (MMC).