Although Alzheimer’s disease (AD) has a polygenic architecture, with numerous associated single-nucleotide polymorphisms (SNPs) identified, the contribution of structural variants (SVs) is unclear. In this study, using long-read (n = 11) and short-read (n = 3,190) sequencing data from the Chinese population, we show that common SVs contribute to AD heritability beyond common SNPs. We identify an expanded CCG repeat in the FAM193B promoter that shows a genome-wide significant association with increased AD risk (odds ratio = 2.20 per 10-repeat increase, P = 5.5 × 10−13).
The expanded FAM193B-CCG repeat increases FAM193B expression and mediates the pleiotropic association between brain FAM193B expression and AD risk. Analyses of postmortem human brains and cultured neuronal cells show that elevated neuronal FAM193B expression is associated with DNA damage and cell death-related pathways. These findings establish the common FAM193B-CCG repeat as an AD risk genetic factor and highlight the contribution of common SVs to AD heritability.
AD, a progressive neurodegenerative disorder, is the most common type of dementia and one of the leading causes of death in the aged population1. AD is highly heritable and exhibits polygenic architecture2. Genome-wide association studies (GWASs) have identified more than 70 risk loci for AD3.
Most identified AD risk genetic variants are common variants with minor allele frequency (MAF) > 0.05, such as APOE ε4, which is the most significant AD risk genetic variant and has high disease penetrance (odds ratio (OR) = 3.2 for heterozygous carriers)4. Although other common genetic variants exert relatively weak effects on AD risk, their polygenic effects account for a substantial proportion of heritability5. Nonetheless, the known AD-associated genetic variants do not fully explain the observed heritability of AD2, indicating the presence of unidentified disease-associated genetic factors.
Existing genetic studies are limited by their focus on small genetic variants, such as SNPs. Consequently, the disease associations of SVs, which affect genomic regions larger than 50 base pairs, are largely overlooked6. Compared to SNPs, SVs affect more nucleotide content in the human genome and play a role in disease susceptibility7.
Indeed, genetic studies illustrate strong risk effects of rare SVs on AD and other neurodegenerative diseases8,9,10,11. For example, duplication of APP is reported to cause autosomal dominant AD in a few families11. Recent genetic studies on SVs and tandem repeat expansions reveal an increased polygenic burden of rare SVs in patients with sporadic AD12,13.
Extract — continue reading at the source.
