Alzheimer Disease Genetics

Consortium: Organization & Progress

Lindsay A. Farrer

Genetics Program

Boston University School of

Medicine

International Conference on Alzheimer Disease

July 11, 2010 Honolulu

• Identify genetic variants that cause AD

• Identify genetic variants that increase risk for AD

• Identify genetic variants that affect AD endophenotypes(Aβ load, tangle load, psychosis, biomarker levels, etc.)

Goals

• Identify genetic variants that cause AD

• Identify genetic variants that increase risk for AD

• Identify genetic variants that affect AD endophenotypes(Aβ load, tangle load, psychosis, biomarker levels, etc.)

Bring together AD investigators, datasets, and resources for large genome wide

association studies of AD and related traits

Solve the genetics of Alzheimer disease

Goals

• Acquire and assemble existing GWAS datasets

• Acquire and genotype de novo samples from ADCs and population-based studies using high-density SNP platforms

• Analyze all GWAS datasets using a variety of approaches

• Assemble and analyze data from a replication cohort

Mechanism

July 2007: small NIA-organized planning meeting

August 2007: large comprehensive NIA-organized meetingADGC is formed

November 2007: NIA funds NACC/NCRAD for initial sample collection

April 2008: Private foundation funds initial ADGC analyses using existing GWAS datasets

April 2009: UO1 is funded

August 2009: initial genotyping completed (2,100 subjects)

History of the ADGC

ADGC Projects – year one/two

1. Analysis of existing GWAS datasets

2. Genotyping and analysis of ADC autopsy cases/controls

3. Genotyping and analysis of ADC Uniform dataset (UDS) clinical cases/controls

4. AD GWAS including all available datasets

5. GWAS of CSF biomarker traits

Washington University: 431University of Washington: > 500

ADNI: 491*University of Pennsylvania: 283

* Not funded by the ADGC but data is/will be available

6. GWAS analysis of prospective cohorts (European Ancestry)

ADGC Projects – years two thru five

incident incidentCohort PI n > 3 evals. dementia MCI

CHAP Evans 2,300 1,500 210 270

WHICAP Mayeux 904 586 59 105

MAP Bennett 1,050 950 150 250

WHISCA Resnick 2,275 2,000 85 170

ACT* Larson 2,100 ~300

ADPR* Kukull ~300

* Not funded by the ADGC but data is/will be available

Administration – UPenn teamExternal Advisory

CommitteeInvestigator Committee

ADGC Organization

Executive Committee

Administration – UPenn team

Familial AD Committee

Prospective Cohort

Committee

External Advisory

Committee

Analysis Committee

Neuropath. Committee

Biomarker Committee

Investigator Committee

Clinical Committee

ADGC Organization

Executive Committee

29 ADCs

Bud Kukulldata

cleaning

Alzheimer’s Disease Center Samples

NACC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

Selection of samples for GWASNACC

ADGC

Bud Kukull

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

Selection of samples for GWAS

Autopsy SamplesNeuropathology committee

• Thomas Montine: chair, co-PI• Eric Reiman: co-PI• Dennis Dickson• Matthew Frosch• Bernadino Ghetti• Brad Hyman• Julie Schneider• John Trojanowski

• Walter Kukull NACC• Gerard Schellenberg ADGC

NACC

ADGC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

Selection of samples for GWAS

subject lists

Autopsy SamplesNeuropathology committee

• Thomas Montine: chair, co-PI• Eric Reiman: co-PI• Dennis Dickson• Matthew Frosch• Bernadino Ghetti• Brad Hyman• Julie Schneider• John Trojanowski

• Walter Kukull NACC• Gerard Schellenberg ADGC

NACC

ADGC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

Selection of samples for GWAS

UDS SamplesClinical committee

• John Morris chair, co-PI• Debbie Tsuang co-PI• Thomas Bird• Helena Chui• Jeffrey Cummings• Charlie DeCarli• Steven Ferris • Douglas Galasko• Neil Graff-Radford• Richard Mayeux• Elaine Peskind• John Ringman• Sandra Weintraub• Walter Kukull NACC• Gerard Schellenberg ADGC

subject lists

NACC

ADGC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

subject lists

NCRAD

DNAtissue

Tatiana Foroud

NACC

ADGC

ADGC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

subject lists

DNAtissue

list of samples received

NACC

ADGC

NCRAD

ADGC

29 ADCs

data

cleaning

Alzheimer’s Disease Center Samples

subject lists

DNAtissue

list of samples received

Genotyping site

CHOP

DNA

NACC

ADGC

NCRAD

ADGC

Alzheimer’s Disease Center Samples

29 ADCs

data

cleaning

subject lists

DNAtissue

list of samples received

Genotyping site

CHOP

DNA

ADGCUPenn

genotype data

phenotype data

NACC

ADGC

NCRAD

ADGC

OTHER GWASDATASETS

Special analysis groups (SAGs)

• clean genotype data• impute genotypes• merge genotype/phenotype data• Perform primary analyses

University of Miami analysis group

Boston University analysis group

Margaret Pericak-Vance Lindsay Farrer

Genotyping

ADGCUPenn

genotype data

phenotype data data

Special analysis groups (SAGs)

• clean genotype data• impute genotypes• merge genotype/phenotype data• Perform primary analyses

University of Miami analysis group

Boston University analysis group

Margaret Pericak-Vance Lindsay Farrer

data

dbGaP

NIAGADUPenn

ApoEGWAS SNPsCNV data

ADCs

publication

ADGC Website

http://alois.med.upenn.edu/adgc/

Autopsy samples

genotyped by the

ADGC

Cases: 2,901Controls: 211

Autopsy samples

with NACC data

Overlap with

other studies

Remaining

samples

Samples received

Percent

recovered

4,727

764

3,963

3,773

95.2%

Clinical samples

genotyped by the

ADGC

Cases: 1,216Controls: 1,791

Clinical UDS

samples in NACC

Samples received

Demented (AD)

Normal

MCI

excluded

17,270

1,543

6,033

2,130

1,554

806

CSF samples

genotyped by the

ADGC

Cases: 98Controls: 155MCI: 11Other: 119Total: 383

Pending: 76

Current total: 459

Projected Total: >600

ADGC Study to Replicate CR1, CLU and PICALM

Association Findings in European Consortia GWAS

CohortNumber

of Cases

Number

of

autopsies

Mean

onset age

(SD)

Number

of

Controls

Number

of

autopsies

Mean age at

last exam

(SD)

Total

Percent of

Ethnic

group

Caucasian Subjects

ADC 1,595 1,421 73 (7.7) 553 134 77 (8.7) 2,148 17%

ADNI 286 0 74 (8.1) 195 0 78 (5.4) 481 4%

CAMP 127 0 79 (7.9) 105 0 76 (7.8) 232 2%

FHS 197 0 83 (6.4) 2,392 0 73 (7.5) 2,589 20%

UM/VU/MSSM 1,170 370 74 (7.7) 1,169 75 74 (7.6) 2,339 18%

MIRAGE 560 0 71 (6.5) 790 0 72 (7.1) 1,350 10%

NIA LOAD 993 367 72 (6.9) 884 45 76 (8.4) 1,877 14%

OHSU 187 215 87 (7.3) 429 461 86 (7.2) 616 5%

TGEN 820 613 80 (8.3) 517 377 83 (8.9) 1,337 10%

Totals 5,935 2,986 7,034 1,092 12,969 100%

African American Subjects

ADC 61 61 75 (7.0) 63 63 76 (6.2) 124 14%

JHU 221 0 77 (6.6) 186 0 78 (6.6) 407 45%

MIRAGE 180 0 70 (8.9) 200 0 71 (10.0) 380 42%

Totals 462 61 449 63 911 100%

Arab Subjects

Wadi Ara 124 0 78 (7.9) 142 0 72 (6.0) 266 100%

Caribbean Hispanic Subjects

Columbia 549 8 80 (8.0) 544 0 79 (6.4) 1,093 100%

All Ethnic Groups

Totals 7,070 3,055 8,169 1,155 15,239

SD: Standard deviation; ADC: Alzheimer Disease Centers cohort; ADNI: Alzheimer Disease Neuroimaging Initiative cohort; FHS.: Framingham Heart Study

cohort; UM/VU/MSSM: University of Miami/Vanderbilt University/Mt. Sinai School of Medicine cohort; MIRAGE: Multi Institutional Research on Alzheimer's

Genetic Epidemiology cohort; NIA LOAD: National Institute on Aging Late-onset Alzheimer Disease cohort; OHSU: Oregon Health Sciences University cohort;

TGEN: Translational Genomics Research Institute cohort

Unadjusted adjusted age sex & APOE

SNP MA MAF OR 95% CI P‡ OR 95% CI P‡

CR1

rs3818361 A 0.26 1.14 1.07 - 1.22 6.1x10-5 1.15 1.07 - 1.24 0.0002

rs6701713 A 0.26 1.14 1.07 - 1.22 8.8x10-5 1.15 1.07 - 1.24 0.0002

rs1408077 A 0.26 1.14 1.07 - 1.22 0.0001 1.16 1.07 - 1.25 0.0002

CLU

rs7012010 C 0.39 1.10 1.03 - 1.17 0.0025 1.10 1.02 - 1.17 0.0081

rs3087554 C 0.16 1.00 0.92 - 1.09 0.92 0.98 0.89 - 1.08 0.71

rs11136000 T 0.43 0.91 0.85 - 0.96 0.0007 0.92 0.86 - 0.98 0.0096

rs9331888 G 0.25 0.99 0.92 - 1.06 0.76 0.99 0.91 - 1.07 0.74

rs7982 T 0.38 0.87 0.81 - 0.94 0.0002 0.89 0.83 - 0.97 0.0046

PICALM

rs532470 G 0.49 1.06 1.00 - 1.11 0.048 1.02 0.96 - 1.09 0.47

rs592297 C 0.20 0.92 0.86 - 0.99 0.02 0.96 0.89 - 1.04 0.33

rs677909 C 0.40 0.88 0.83 - 0.94 3.3x10-5 0.94 0.88 - 1.00 0.056

rs636848 G 0.24 1.02 0.96 - 1.08 0.6 1.00 0.93 - 1.07 0.98

rs541458 C 0.39 0.88 0.83 - 0.93 2.6x10-5 0.94 0.88 - 1.00 0.048

rs561655 G 0.29 0.89 0.84 - 0.94 3.4x10-5 0.92 0.87 - 0.99 0.017

rs543293 A 0.36 0.88 0.83 - 0.93 2.3x10-5 0.92 0.86 - 0.98 0.015

rs7941541 G 0.28 0.89 0.83 - 0.95 0.0007 0.95 0.88 - 1.03 0.21

rs3851179 T 0.35 0.89 0.84 - 0.94 3.9x10-5 0.93 0.87 - 0.99 0.026

Jun et al. Arch Neurol 2010 In press.

Gene/SNP

APOE e4 (-)† APOE e4 (+)† SNP*APOE interaction¶

OR 95% CI P-value OR 95% CI P-value OR 95% CI P-value

CR1

rs3818361 1.10 1.02 - 1.19 0.0170 1.14 1.03 - 1.26 0.0120 1.01 0.99 - 1.03 0.2800

rs6701713 1.10 1.01 - 1.19 0.0210 1.14 1.03 - 1.26 0.0110 1.01 0.99 - 1.04 0.2800

rs1408077 1.06 1.00 - 1.12 0.0360 1.15 1.03 - 1.27 0.0099 1.06 0.97 - 1.16 0.1900

CLU

rs7012010 1.10 1.00 - 1.20 0.0430 1.05 1.00 - 1.10 0.0640 1.03 0.94 - 1.12 0.5100

rs3087554 1.01 0.90 - 1.14 0.8800 1.00 0.84 - 1.18 0.9700 1.00 0.82 - 1.22 1.0000

rs11136000 0.91 0.84 - 0.98 0.0150 0.93 0.84 - 1.03 0.1700 0.98 0.92 - 1.06 0.6500

rs9331888 1.03 0.93 - 1.14 0.5300 0.92 0.80 - 1.05 0.1900 0.89 0.77 - 1.04 0.1400

rs7982 0.87 0.79 - 0.97 0.0092 0.92 0.81 - 1.05 0.2200 1.06 0.91 - 1.24 0.4800

PICALM

rs532470 0.99 0.92 - 1.08 0.8900 1.12 1.01 - 1.24 0.0300 1.11 0.98 - 1.25 0.1000

rs592297 1.04 0.97 - 1.11 0.3200 0.90 0.79 - 1.03 0.1200 0.85 0.73 - 1.00 0.0480

rs677909 0.99 0.91 - 1.08 0.8000 0.86 0.77 - 0.96 0.0062 0.86 0.75 - 0.98 0.0260

rs636848 0.96 0.88 - 1.06 0.4400 1.07 0.95 - 1.21 0.2700 1.07 0.92 - 1.23 0.3900

rs541458 0.99 0.91 - 1.08 0.8100 0.86 0.77 - 0.96 0.0066 0.86 0.75 - 0.98 0.0270

rs561655 0.97 0.89 - 1.06 0.5000 0.83 0.75 - 0.93 0.0009 0.82 0.73 - 0.93 0.0024

rs543293 1.00 0.92 - 1.09 0.9800 0.83 0.74 - 0.93 0.0011 0.81 0.71 - 0.93 0.0026

rs7941541 0.98 0.90 - 1.08 0.7300 0.90 0.79 - 1.02 0.0990 0.89 0.79 - 0.99 0.0360

rs3851179 0.99 0.91 - 1.07 0.7300 0.86 0.77 - 0.95 0.0034 0.84 0.74 - 0.95 0.0068

Jun et al. Arch Neurol 2010 In press.

Cohorts for ADGC GWAS

Cohort Ethnicity Cases Controls Total Platform

CR1, CLU,

Picalm

Replication

ADGC

GWAS

ADGC

GWAS

replication

AA

ADNI Caucasian 291 189 480 Illumina 550K X X

OHSU Caucasian 424 169 593 Illumina 300K X X

NIA LOAD Caucasian 1,839 1,983 3,822 Illumina 610Q X X

Miami/Vanderbilt/Mt.Sinai Caucasian 1,168 1,168 2,336 Illumina 550K X X

MIRAGE Caucasian 603 885 1,488 Illumina 660 Quad X X

ADC Caucasian 2,321 916 3,237 Illumina 660 Quad X X

GSK Caucasian 656 641 1,297 Affymetrix 550K X

TGEN Caucasian 744 420 1,164 Affymetrix 6.0 X X

eMERGE (ACT) Caucasian 567 1,701 2,268 Illumina 660 Quad X

Washington Univ. Caucasian 406 178 584 Illumina 610 Quad X

CAMP Amish 127 105 232 Illumina 550K X X

Framingham Caucasian 197 2,392 2,589 Affymetrix 550K X X

NIA-ADC June 2010 Caucasian 1,015 697 1,712 Illumina Omni Express X

Mayo Clinic Caucasian 844 1,255 2,099 Illumina 300K X

ROS/MAP Caucasian 495 1,153 1,648 Affymetrix 6.0 X

Univ. Pittsburgh Caucasian 1500 1,500 3,000 X

MIRAGE AA 260 240 500 Illumina 660 Quad X X

NIA-ADC AA 61 63 124 Illumina 660 Quad X X

NIA-ADC June 2010 AA 183 123 306 Illumina Omni Express X

GenerAAtions AA 250 218 468 Illumina 660 Quad X X

Columbia Hispanic 549 544 1,093 Illumina 650Y X

Wadi Ara Israeli-

Arab124 142 266 Illumina 370K X

Cases Controls Total

Caucasian Discovery * 8,613 8,072 16,685

Caucasian Replication 4,584 7,280 11,864

African American † 754 1,398 2,152

* ~ 2-fold larger than the largest of published AD GWAS

discovery samples

† effort underway to increase this sample 3-4 fold

Cohorts for ADGC GWAS

ADGC Projects in progress and on-deck

• GWAS in Caucasians

• Assemble large African American cohort for GWAS

• GWAS of endophenotypes in case/control group (e.g., biomarkers, neuropathological traits)

• Prospective cohort studies

David Bennett Rush University Medical Center, Chicago, IL Deborah Blacker Massachusetts General, Boston, MALindsay Farrer Boston UniversityTatiana Foroud Indiana University, Indianapolis, INAlison Goate Washington University, St Louis, MOJonathan Haines Vanderbilt, Nashville, TNHakon Hakonarson Children’s Hospital of Philadelphia, Philadelphia, PAWalter Kukull University of Washington, Seattle, WAKathryn Lunetta Boston University, Boston, MA Eden Martin University of Miami, Miami, FLRichard Mayeux Columbia University, New York, NYThomas Montine University of Washington, Seattle, WAJohn Morris Washington University, St Louis, MO Margaret Pericak-Vance University of Miami, Miami, FLEric Reiman Banner Alzheimer’s Institute, Phoenix, AZAndrew Saykin Indiana University, Indianapolis, INGerard Schellenberg (PI) University of Pennsylvania, Philadelphia, PADebbie Tsuang University of Washington, Seattle, WA

Laura Cantwell University of Pennsylvania, Philadelphia, PALi-San Wang University of Pennsylvania, Philadelphia, PA

Funding: NIA - UO1/GO grants, Boston non-profit foundation

KUDOS

Boston University

Gyungah JunJacki BurosBadri Vardarajan

University of Miami

Gary BeechamAdam NajPaul Gallins

Special Thanks

The Clinical and Neuropathology

Cores of the NIA-sponsored

Alzheimer Disease Centers