LMTK2 and CRB1 are two novel risk genes for Alzheimer's disease in Han Chinese.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with a substantial genetic background. However, its underlying genetic architecture remains to be elucidated.

Methods: In this study, we performed whole-exome sequencing in 282 familial and/or early-onset AD patients and 1086 cognitively normal controls in the Han Chinse populations. According to minor allele frequency, variants were divided into common variants (MAF ≥ 0.01) and rare variants (MAF < 0.01). Common variant-based association analysis and gene-based association test aggregating rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. We replicated the significant results by using the same AD samples and controls from whole genome sequencing (n = 1879). Furthermore, we determined the functions of the novel AD risk genes in vitro.

Results: Common variants association analysis revealed that APOE rs429358 reached statistical whole-exome significance. Gene-level aggregation testing identified that rare damaging variants in LMTK2 and CRB1 conferred risk to AD. All variants are located in highly conserved amino acid regions and are predicted to be damaging. Furthermore, functional studies showed that LMTK2 rare damaging variants (R234P and S974G) enhanced tau phosphorylation levels, tau aggregates formation, and Aβ generation. Meanwhile, the CRB1 Y556X variant caused incomplete translation of CRB1 protein and increased the Aβ42 level and Aβ42/Aβ40 ratio.

Conclusion: Our findings indicated that LMTK2 and CRB1 are two novel AD risk genes in Han Chinese, which may provide promising targets for diagnosis and intervention.