ADSP-FUS2 WGS

The ADSP-FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late-onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial-ethnic diversity. The ADSP-FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data to expand the utility of new discoveries for individuals from all populations.

ADSP FUS2 samples were whole-genome sequenced at either at the University of Miami on the HiSeqX or USUHS on the NovaSeq machine. 13228 samples were sequenced and FASTQ files were sent to GCAD for processing on the VCPA1.1 pipeline. A total of 12,621 samples passed sequencing metrics and quality control checks.

Brief descriptions of the 17 individual datasets sequenced in FUS2 are provided below. Counts below may not be the final number of genomes released in this dataset, but instead what were sent for sequencing. Detailed descriptions of the datasets can be found below.

ADSP-FUS2-ADC-AA, ADSP-FUS2-ADC-Amerindian, and ADSP-FUS2-ADC-Hispanics
The Alzheimer’s Disease Research Center (ADRC) Cohorts, which includes Black/African American, Amerindian, and Latino/Hispanic specific cohorts, are selected from the National Institute on Aging’s ADRC’s, a network of 38 academic centers across the United States focused on AD and Alzheimer’s Disease Related Dementias research.

ADSP-FUS2-AmishPV
The Amish Protective Variant Study, based at Case Western Reserve University and the University of Miami (Cummings et al. 2012; D’Aoust et al. 2015), is being conducted in the Indiana and Ohio Old Order Amish population. This population is an isolated founder population originating from immigration of German and Swiss Anabaptists to the United States in the 1700’s and 1800’s. Approximately 840 individuals from the study have been sequenced and included in the ADSP-FUS.

ADSP-FUS2-CuAADI
The Cuban American Alzheimer’s Disease Initiative (CuADI) is a convenience sample ascertained through community outreach to Alzheimer’s and adult day care centers in Southern Florida, lay conferences, and Neurology and Memory Disorders clinics. All participants underwent a standard protocol which included collection of sociodemographic information, detailed clinical history, and cognitive screening (3MS). In addition, behavioral measures (GDS, CSDD, and NPI-Q) and functional (ADL) assessments are available. Standard neurocognitive data is available on all individuals.

ADSP-FUS2-CWAutopsy1
The Case Western Reserve University (CWRU) Autopsy Cohort was an ADRC clinic-based sample. Medical records are available on all cases and controls, all of who were tested before death for cognitive function.

ADSP-FUS2-CW-RapidDecline1
The Case Western Reserve University (CWRU) Rapid Decline Cohort (Cohen et al. 2015) represents patients with rapid decline. Through the National Prion Disease Pathology Surveillance Center, CWRU has identified 300+ aged individuals who have classical AD pathology upon autopsy but whose course is very short: from six months to three years. This course is more typical of a prion disease; however, these individuals have been tested for and do not have any prion disease. The amyloid in the amyloid plaques has a slightly different protein structure, suggesting that that rpAD has a different genetic architecture than typical late-onset AD (LOAD). Additionally, sequencing of the APP gene did not identify any novel or known pathogenic variation. rpAD has not been genetically examined and the 300+ autopsy confirmed AD cases would significantly increase the pool of confirmed cases. Substantial clinical data are available on most cases, and additional samples of blood, plasma, CSF and RNA are available on a subset, greatly increasing their potential value.

ADSP-FUS2-EFIGA
The Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) Study is a study of late-onset AD patients with Caribbean-Hispanic ancestry being conducted at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York City (Vardarajan et al. 2014). Families and unrelated individuals were recruited as a part of a family-based study: Estudio Familiar de Influencia Genetica en Alzheimer, based in the Dominican Republic. All individuals undergo standard neuropsychological tests and neurological examinations to verify their clinical status and for diagnoses based on NINCDS-ADRDA criteria for probable or possible LOAD.

ADSP-FUS2-EOAD1
The ADGC Early Onset Alzheimer Disease (EOAD) Cohort is a sample set consisting of ~1,400 EOAD cases available through the Alzheimer Disease Genetics Consortium (ADGC). All samples are early onset (AAO<65), with available DNA and phenotyping (through the Uniform DataSet). This sample set is expected to have minimal known mutations (APP, PSEN1, PSEN2, SORL1 etc). A significant subset of the sample has autopsy information and/or information on family history providing the opportunity to generalize variants identified to neuropathological endophenotypes and to assess whether variants identified are unique to families multiply affected by the disease or also play a role in sporadic EOAD.

ADSP-FUS2-IBADAN
The Indianapolis-Ibadan Study of Aging is a longitudinal study begun in 1991 in Indianapolis, Indiana and Idikan Ward of Ibadan city, Nigeria (Hendrie et al. 1995; Osuntokun et al. 1995). Study participants in the Ibadan cohort belong to the Yoruba ethnic group who inhabit south-western Nigeria and extend to neighboring Benin Republic to the west, which is the primary origin of the African ancestry in African Americans. The Ibadan portion of the study currently has 79 cases, 176 MCI, and 759 controls aged 65 years or older that have been sequenced and included in the ADSP-FUS. The African American samples from the Indianapolis cohort have been sequenced in the ADSP as part of the ADGC AA cohort. The AD cases from this cohort are the first and only African AD cases with WGS, making their sequencing an essential first step towards inclusion of this completely unrepresented group in AD research.

ADSP-FUS2-MHAS
The Mexican Health and Aging Study (MHAS), sponsored by the National Institutes of Health (NIH) National Institute on Aging (NIA), is prospective study of health and aging in Mexico that began in 2001 (MHAS 2001). The ADSP FUS will sequence 200 MHAS cases and 2,600 MHAS controls from this study starting in 2019.

ADSP-FUS2-Miami-BrainBank
The University of Miami Brain Bank Cohort was ascertained through self-referred cases and controls to the University of Miami Brain Endowment Bank, a National Institutes of Health (NIH) NeuroBioBank, one of six designated brain and tissue biorepositories in the nation. Medical records are available on all cases and controls, all of who were tested before death for cognitive function.

ADSP-FUS2-NOMAS
The Northern Manhattan Study (NOMAS), funded by the NIH’s NINDS, is a study focused on stroke or related neurological syndromes (Sacco et al. 2004). The ADSP FUS will sequence 88 Hispanic cases and 175 Hispanic controls, and 22 African-American cases and 43 African-American controls from this study starting in 2020.

ADSP-FUS2-PeADI
The Peru Alzheimer’s Disease Initiative (PeADI) is being conducted at several sites in Peru including Lima (Marca-Ysabel et al. 2021). The Mestizo population living in Lima, the capital city, is comprised of ~76% of Amerindian, 11% Southern European, and 3% Northern African ancestries, and a smaller proportion of western central Africa, western central Europe, Finland, northern Siberia and Jewish diaspora. Cases will be clinic based and controls will be clinic and community based. With few Amerindian individuals available for study, the inclusion of a Peruvian cohort will enhance the admixture studies proposed in CADRE and other groups in the ADSP analysis phase.

ADSP-FUS2-PRADI
The Puerto Rican Alzheimer’s Disease Initiative (PRADI) is a NIH NIA study of late-onset Alzheimer disease focused on the Caribbean-Hispanic Puerto Rican population. The ADSP FUS will sequence 500 cases and 500 controls from this study starting in 2020.

ADSP-FUS2-REAAADI
The Research in African-American Alzheimer’s Disease Initiative (REAAADI) is a NIH NIA study focused on identifying genetic factors for Alzheimer disease within the African-American population in order to detect new targets for drug development and improve accessibility to Alzheimer’s disease education within the community. The ADSP FUS will sequence 300 cases and 300 controls from this study starting in 2020.

ADSP-FUS2-StEPAD2
Stanford Extreme Phenotypes in AD (StEP AD). The overall goals of the Stanford Extreme Phenotypes in AD (StEP AD) project (Dr. Michael Greicius) are to identify and characterize novel genetic variants that promote resilience to AD pathology in the presence of the APOE4 allele or that drive pathogenesis in the absence of the APOE4 allele. Genomes are collected from several sources, some intramural and some extramural. Invariably, the cognitive assessment protocols for these different sources vary somewhat but all include APOE genotyping, extensive neuropsychological testing, collection of one or more AD biomarkers, and consensus adjudication.

Genomes were sequenced for subjects in the following three categories:

1. Protected APOE4 carriers that have the APOE3/4 genotype, are at least 80 years old, and have normal cognition. If additional follow-up is expected we will accept subjects as young as 77.
2. Super-protected APOE4 carriers that have the APOE4/4 genotype, are at least 70 years old, and have normal cognition. If additional follow-up is expected we will accept subjects as young as 67.
3. APOE4-negative, early-onset cases that have the APOE2/2, 2/3, or 3/3 genotype and are diagnosed with probable AD before age 65. Most are also negative for known PSEN1, PSEN2 or APP mutations.

Funding for this project comes from the NIA (1R01AG060747).

ADSP-FUS2-WRAP
The Wisconsin Registry for Alzheimer’s Prevention (WRAP) Study is comprised of individuals from a registry begun in 2011 that includes more than 1,700 individuals, followed over time, to learn about biological, health, and lifestyle factors that may affect Alzheimer’s disease. The data set includes information on cognition, lifestyle, physical activity, biomarkers, genetics and metabolism.

ADSP-FUS2-Replicates
The six subjects run as technical replicates in the ADSP Discovery and Discovery Extension were also sequenced by USUHS as part of the ADSP FUS. There were 18 samples total with the six subjects run three times each. The 3 runs are as follows: 1) HiSeqX via a single lane, 2) HiSeqX via multiple lanes, and 3) Novaseq via multiple lanes.