Genetic ancestry of human induced pluripotent stem cells banked for neurodegeneration research

Abstract

AbstractBackgroundThe National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) has established a centralized repository for human induced pluripotent stem cells (iPSCs) and fibroblasts in partnership with the National Institute on Aging (NIA). This is a critical resource for the research community, which can facilitate disease modeling, functional genetic studies, and drug development. However, the utility of this resource is still limited in terms of racial and ethnic diversity, which has the potential to bias neurodegenerative research and drug development unless steps are taken to create and share a more diverse array of cell lines.MethodAt NCRAD, banked iPSCs are subjected to quality control including short‐read whole genome sequencing (WGS). 78 samples have been submitted for sequencing; of these, data for 51 have been returned and analyzed, including multiple isogenic lines from three donors. WGS data was aligned, and quality control performed using Sentieon software, following GATK best practices. Data was combined with sequencing data from 2,548 1000 Genomes participants and pruned in PLINK. R package SNPRelate was used to generate a kinship matrix and perform principal component analysis (PCA). Clustering analysis was performed utilizing K‐means clustering to group samples into 5 clusters. PCs 1‐3 were graphed, color‐coded by cluster, and final ancestry calls reviewed for clustering with reference groups.ResultThe NCRAD 51 iPSC lines with analyzed WGS data were sourced from 28 neurodegenerative cases and 12 controls. In this data set, 83% of samples (89% of cases, 67% of controls) have European ancestry. The cohort also includes one case and one control line of East Asian ancestry, as well as 2 cases and 3 controls showing admixture of European/American ancestry. 17 individuals did not have reported race/ethnicity, while 2 controls showed genetic admixture though reported as White non‐Hispanic, and the remaining individuals’ genetic ancestry matched reported race/ethnicity.ConclusionCentralized banking of iPSCs from individuals with neurodegenerative diseases is creating a key resource to advance research; however, to date the diversity of these samples is limited. We urge researchers to develop and share more diverse cell lines, to promote diversity and equity in neurodegenerative research.