Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

Dmitry Prokopenko,Yuriko Katsumata,Christoph Lange,Sarah Morgan,Kristina Mullin,Nan Laird,Winston Hide,Julian Hecker,Rudolph E Tanzi,Lars Bertram,David W Fardo,Michael W Weiner,Sanghun Lee

doi:10.1038/s41380-022-01475-0

Dmitry Prokopenko, Yuriko Katsumata + Show 11 more

Open Access

https://doi.org/10.1038/s41380-022-01475-0

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Abstract

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

Highlights

Alzheimer’s disease (AD) is a heterogeneous, genetically complex neurodegenerative disorder [1]
RNA-Seq and microarray analysis We explored Discs large homolog 2 (DLG2) and dystobrevin beta (DTNB) genes’ expression based on the Human Protein Atlas (HPA) RNA-seq data (URLs) and tested for differential expression of synaptic and immune-related genes including DLG2 and DTNB genes between normal controls (N = 173, aged 20–99 years) and AD cases (N = 80) in the brain regions including hippocampus, entorhinal cortex, superior frontal cortex, and post-central gyrus using microarray dataset GSE48350, which is available from the Gene Expression Omnibus Web site (URLs)
In a region-based whole-genome sequencing rvGWAS focusing on rare genomic variants, we combined two AD family-based cohorts, the National Institute of Mental Health (NIMH) Alzheimer’s disease genetics initiative study (NIMH) and the family component of the NIA ADSP sample

Summary

Introduction

Alzheimer’s disease (AD) is a heterogeneous, genetically complex neurodegenerative disorder [1]. Over the past 15 years, around 120 genome-wide association studies (GWAS) have been performed to elucidate the genetic architecture underlying AD according to the GWAS catalog [2]. The latest GWAS which has utilized over 1 million individuals ascertained from clinical and proxy-based AD cases and controls has identified 38 independent loci to be associated with AD [3]. GWAS heritability which is tagged by common variants is estimated to be 24-33% [4, 5] - less than a half of the heritability calculated from twin studies [1]. Identification of rare variants associated with AD may help explain the missing heritability, and lead to new biological insights [6]. Several rare variant loci previously associated with AD [7], including TREM2 [8, 9], have been identified with whole-exome sequencing (WES) studies [10]

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