Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics

Zihuai He, Yann Le Guen, Linxi Liu, Justin Lee, Shiyang Ma, Andrew C. Yang, Xiaoxia Liu, Jarod Rutledge, Patricia Moran Losada, Bowen Song, Michael E. Belloy, Robert R. Butler, Frank M. Longo, Hua Tang, Elizabeth C. Mormino, Tony Wyss-Coray, Michael D. Greicius, Iuliana Ionita-Laza

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

Original languageEnglish
Pages (from-to)2336-2353
Number of pages18
JournalAmerican journal of human genetics
Issue number12
StatePublished - Dec 2 2021


  • Alzheimer disease
  • GWAS
  • knockoff statistics
  • omics
  • sequencing


Dive into the research topics of 'Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics'. Together they form a unique fingerprint.

Cite this