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2018 Family-Based Study

The Alzheimer Disease Sequencing Project (ADSP) Family Based Study
The ADSP has generated whole genome sequence (WGS) data from members of families multiply affected by late onset Alzheimer’s disease (LOAD).  The WGS data was included 582 individuals from 111 multiplex AD families of European or Caribbean Hispanic ancestry, favoring families with multiple cases across generations excluding families with higher frequency of the APOE ε4 allele. Among these 582 individuals, 498 were clinically diagnosed with probable or definite LOAD, with 11% neuropathologically-confirmed. These genomes represent families with European-American, Caribbean Hispanic, and Dutch ancestry. The families were ascertained from multiple sites, including contributors to the Alzheimer Disease Genetics Consortium (ADGC), and the neurology working group of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE). These data are available through the database of Genotypes and Phenotypes (dbGaP; Study Accession: phs000572.v7.p4) and additional information can be found in "The Alzheimer's Disease Sequencing Project: Study design and sample selection". 
WGS data were generated at Baylor University, the Broad Institute, and Washington University. Sequencing, variant calling, and quality control (QC) methods were completed by the ADSP investigators. Read data were initially aligned to the GRCh37-Lite reference genome using the Burrows Wheeler Aligner (BWA, v0.6.2), but this is currently being updated to GRCh38.  These data will be released by the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Variants were called using both the Genome Analysis Tool Kit (GATK)-HaplotypeCaller and Atlas V2pipelines. Discrepancies between the GATK and Atlas V2 calls were reconciled by the ADSP QC Working Group to create the “consensus” data set. This QC protocol involved the development of scripts in the Python, Perl, and R (v2.15 and v3.1.1) languages, as well as the software programs PLINK (v1.07 and v1.9) and PedCheck(v1.2).  APOE genotypes were provided by contributing centers.
To augment the ADSP Discovery phase, the ADSP WGS Discovery Extension project included 83 additional CH individuals and 1 additional CH family, 167 additional Caucasian individuals and 6  new families from the families described above, 48 individuals from 6 new African American families, an additional 147 controls of Caribbean Hispanic ancestry. These data also underwent similar QC methods and were aligned to GRCh38.  These data are also being made publicly available.
Through a collaboration between Columbia University and the New York Genome Center, 303 additional families (1132 family members) of white, non-Hispanic European ancestry, 27 African Families (57 individuals) and 219 additional families (1788 family members) of Caribbean Hispanic ancestry have undergone WGS.  The first phase of the data has been sequenced and QC and alignment is underway by the ADSP investigators. The full dataset is expected to be publically available in Summer of 2018.

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