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ADGC) Collaboration and Data Sharing Summary Alzheimer’s Disease Genetics Consortium (ADGC) Collaboration and Data Sharing Summary Alzheimer’s Disease Genetics Consortium (ADGC) NIA grant U01AG032984 Collaboration and Data Sharing Summary ADGC lead investigators Gerard D. Schellenberg, PI: University of Pennsylvania Lindsay Farrer: Boston University Jonathan Haines: Case Western Reserve University Richard Mayeux: Columbia University Margaret Pericak-Vance: University of Miami Li-San Wang: University of Pennsylvania The ADGC was formed to collaboratively use the collective resources of the AD research community to identify Alzheimer’s disease (AD) genes. These genes include those that cause AD, increase or decrease AD risk, and protect against AD. The ADGC includes investigators with the clinical, neuropathological, molecular and statistical expertise needed to analyze the complex phenotype of AD. The ADGC assembled genetic and phenotype data for a large number of AD cases and cognitively normal elderly controls. For non-Hispanic whites (NHW), subjects include 17,876 cases and 19,440 controls (Table 1A). For other ethnic groups (African Americans, Caribbean Hispanic, non-Caribbean Hispanics, and Asians), the subjects include 9,392 AD cases and 15,125 controls (Table 1B). Through a variety of approaches, the ADGC continues to add to this collection of cohorts. The following describes the collaborations established and the data sharing activities of the ADGC. I. ADGC collaborative network. The ADGC collaborates with 21 different cohorts in the US (Table 1A, B). The largest cohort is from the 31 NIA-funded Alzheimer’s Disease Centers (ADC’s) which have contributed 7,428 cases and 7,342 controls to ADGC studies. While the majority of subjects are non-Hispanic Caucasians (Table 1A), the ADGC also assembled and analyzed genetic and phenotype data for Hispanics, African Americans, and Asians (Table 1B). Each of these cohorts has extensive phenotype data that can be used for genetic analysis. A. The ADGC national collaborative network. 1. The 31 ADCs, characterize AD subjects, MCI, and normal controls, and collects blood/DNA for these subjects. The ADCs have provided over 24,267 subjects for ADGC studies including non- Hispanic Whites, Hispanics, African Americans, Native American, and Asian subjects (Table 1A, B). 2. The National Alzheimer’s Coordinating Center (NACC) collects phenotype data from the ADCs. NACC works with the ADGC to identify subjects appropriate for genetic studies and provides phenotype data for these genetic studies. 3. The National Cell Repository for AD (NCRAD) which, in collaboration with the ADGC and NACC, collects blood and DNA from ADCs and other studies. NCRAD then provides these samples to the ADGC for genotyping and sequencing. 4. The National Institute on Alzheimer’s Genetics of Alzheimer’s Disease Storage (NIAGADS) site provides qualified access data sharing for ADGC data. 5. The Alzheimer’s Disease Sequence Project (ADSP) is generating and analyzing DNA sequence data for AD, ADRD, and normal control subjects. The ADGC provides samples, genotype data, and phenotype data to the ADSP for samples undergoing whole exome (WES) and whole-genome sequencing (WGS). Page 1 of 4 Alzheimer’s Disease Genetics Consortium (ADGC) Collaboration and Data Sharing Summary 6. The ADGC generated WES data for ~3,200 African Table 1A. ADGC non-Hispanic White cohorts Americans and will be generating WGS for cohorts from Cohort Cases Controls Other Total Iceland, Mexico, and US Hispanics. These data will be ACT 532 1571 2,103 contributed to the ADSP for joint analyses. ACT3 pending pending 1,551 7. The Principle Investigators of the cohorts listed in Table ADC1 1549 512 2,061 1A are ADGC collaborators. These cohorts provide the ADC2 727 156 883 ADGC with samples, genetic data, and phenotype data ADC3 894 586 1,480 on a collaborative basis. ADC4 304 377 681 ADC5 286 505 791 In addition to these collaborators, the ADGC uses data from multiple public databases such as AMP-AD ADC6 213 338 551 (SAGE), ENCODE, PSYCENCODE, eQTL databases, ADC7 566 878 1,444 multiple expression data sets, MAGMA, dbGaP, and ADC8 517 664 1,181 numerous other sources. ADC9 728 896 1,624 ADC10 457 724 1,181 B. The ADGC and international collaborations. In 1 ADC11 883 1265 2,148 2011 , an international collaboration in AD genetics called ADC12 304 441 377 1,122 the International Genomics Project (IGAP), was founded by the ADGC (Schellenberg) with investigators from Cohorts ADNI 268 173 441 for Heart and Aging Research in Genomic Epidemiology BIOCARD 6 122 128 (CHARGE, Seshadri), European Alzheimer's Disease CHAP 27 144 171 Initiative (EADI, Amouyel), and Genetic and Environmental EAS 9 141 150 Risk in Alzheimer's Disease (GERAD, Williams). IGAP GSK 666 712 1,378 was formed to assemble the largest possible sample to MAYO 658 1046 1,704 increase power for AD genetics studies. ADGC with IGAP MIRAGE 491 738 1,229 published a number of seminal manuscripts on AD MTV 256 189 445 genetics2-4 including the largest genome-wide association NBB 80 48 128 study of AD performed to date (35,274 cases and 59,163 NIA-LOAD 1788 1568 3,356 controls)2. In all, the ADGC/IGAP collaborations produced OHSU 132 153 285 13 primary manuscripts on AD genetics (included in PFIZER 696 762 1,458 Appendix A, pages 1-33). In addition, non-ADGC/IGAP RMAYO 13 233 246 investigators used ADGC/IGAP summary statistics in 47 ROSMAP 354 986 1,340 publications (Appendix A pp 27-33). IGAP is expanding, adding the EADI (Lambert), representing European TARCC 323 181 504 collaborators, and the GRA@CE group from Spain. In TGEN 668 365 1,033 November 2018 and December 2019, IGAP group meetings UCSD ADCS pending pending 1,319 were held in Paris and London, respectively. The following UKS 596 170 766 is a summary of these meetings with detailed information in UMVUMSSM 1177 1126 2,303 Appendices B and C. UPITT 1255 829 2,084 WASHU 339 187 526 1. There were 52 attendees at the 2018 Paris meeting WASHU2 38 94 132 (Appendix B), and 58 attendees at the 2019 London WHICAP 76 560 636 meeting (Appendix C). For both meetings, there were TOTAL 17,876 19,440 377 40,563 attendees from 8 countries, representing 9 global collaborations 2. Countries represented: Belgium, Denmark, France, Germany, Netherlands, Spain, United Kingdom, United States 3. Genetic data from 26 countries: Argentina, Australia, Austria, Belgium, Chile, China, Czech Republic, Denmark, Dominican Republic, Finland, France, Germany, Greece, Iceland, Italy, Japan, Korea, Mexico, Netherlands, Norway, Puerto Rico, Spain, Sweden, Taiwan, United Kingdom, United States Page 2 of 4 Alzheimer’s Disease Genetics Consortium (ADGC) Collaboration and Data Sharing Summary The ADGC has added additional international collaborations with investigators from Korea (Kunho Lee), India (Jinkook Lee, LASI-DAD), Iceland (AGES-RS, Vilmundur Guŏnason) (Appendix D), multiple Caribbean nations, Mexico, Peru, and other South American countries (Pericak-Vance, Mayeux). These new cohorts will be part of future IGAP projects. II. Data Sharing. The ADGC encourages the use of data and attempts to make data available to researchers as soon as possible. In addition to accessing data through dbGaP and NIAGADS, ADGC members can submit analysis proposals to use unpublished data (Special Analysis Groups - SAGs). The ADGC approved 129 data requests through this process, 12 during the past year. Data provided is the latest data set including imputed genotypes, and cleaned phenotype data appropriate for the proposed studies. The genetic data provided has been extensively cleaned and analyzed to account for population stratification, and genotype batch effects. Appendix E lists approved SAGs (pages 1-17). ADGC SAGs include; Total approved SAGs = 129 Average SAGs per year = 14.3 Number of represented institutions = 43 Number of lead investigators = 72 The ADGC data is also available via qualified access from NIAGADS. The GWAS datasets are available as well as secondary analysis results and summary statistics (Appendix F). NIAGADS created a designated page to collate the ADGC data to facilitate finding these data [https://www.niagads.org/resources/related- projects/alzheimers-disease-genetics-consortium-adgc-collection]. Summary statistics are also available for the latest ADGC-IGAP publication through NIAGADS (Appendix F). While individual-level data for ADGC studies are available through NIAGADS, due to the General Data Protection Rule (GDPR) governing European data, individual-level data are not available for the European data used in IGAP publications. IGAP summary statistics were used in 47 publications that are not from IGAP or the ADGC and do not have ADGC authorship (Appendix A, pp 27-33). The ADGC generated whole exome sequence data on 3,159 subjects. These data were analyzed by GCAD and are part of GCAD release 2. Release 2 including the ADGC African American subjects will be released by NIAGADS February 2020after QC is completed. III. Publications. The core analyses, secondary analyses, and SAGs have resulted in 140 ADGC publications, 18 in the past year (Appendix A, pp 1-23). Analyses of genetic data funded by the ADGC account for an additional 31 publications Appendix A, pp 23-27), and 47 publications state the use of IGAP summary statistics which include ADGC data (Appendix A, pp 27-33). (2010-2019) ADGC Publications – 140 (average of 15 publications per year) (2012-2019) Additional Publications using ADGC Supported Studies - 31 (2016-2019) Additional Publications using IGAP Summary Statistics - 47 IV. Member involvement. To support coordination of efforts Table 1B. Ethnicity of ADGC cohorts within the ADGC, the ADGC holds monthly conference calls, ADGC subjects open to all members, to update each other on the status of Ethnic projects and plan the next steps. The ADGC also holds an AD MCI NC Total group annual meeting with an external advisory board. The ADGC NHW 17,876 2,333 19,440 39,649 held its 10th annual meeting in 2019 with 75 members AA 2,845 418 5,271 8,143 attending, representing 24 institutions, including investigators CH 3,859 - 6,365 10,224 from Germany, Canada, and South Korea.
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