Thirteen new rare candidate Alzheimer’s disease (AD) -related sites have been identified. These results were published in Alzheimer’s and dementia.
Whole genome sequencing was performed among 2247 individuals from 605 multiplex AD families. Single variant and spatial clustering-based approaches were used to identify rare candidate locations and regions. An independent cohort of 1669 people was used to replicate these results.
A total of 54,669,406 variants were identified, of which 2% were located in protein-coding exons. Most variants were rare (low allele frequency [MAF] £ 1%, 77% of the variants).
Using a single variant approach, a total of 24,301 rare variants were associated with AD with a significance of P <0.01. No variants achieved genome-wide significance, but the top 271 were significant at P <5 × 10–4.
The regions of rs74065194 (MAF, 0.0066; P = 0.011) and rs192471919 (MAF, 0.0054; P = 0.017) were included in the independent cohort and 2 in a meta-analysis (rs147918541: MAF, 0.0072; P = 2 , 44x) replicates 10-4; rs141228575 / rs147002962: MAF, 0.0069; P = 3.3 x 10-4).
Using a spatial clustering approach, 1756 regions were associated with AD at a significant value of P <0.01. No region achieved genome-wide significance, but the top 47 were significant at P <5 × 10-4.
A total of 4 regions were replicated in the independent cohort (all P £ 1.79 × 10–4) and 6 in a meta-analysis (all P £ 3.27 × 10–5).
When comparing the closest genes identified in the variant and regional analyzes, 90 common genes were identified that were associated with 152 processes and pathways that were enriched for positive regulation of nerve development, heart development, the development of sensory organs, transsynaptic signal transmission and tissue morphogenesis were.
The networks associated with these genes included 1274 interacting proteins, many of which were established AD genes. The highest rated terms in genetic ontology were nervous system development, neurogenesis, and the developmental process.
The researchers identified a total of 13 genes that had never been previously associated with AD:
- APC controller of the WNT signal path (APC)
- open reading frame 41 of chromosome 15 (C15ORF41)
- C2 domain with 3 centriole strain regulators (C2CD3)
- Calsyntenin 2 (CLSTN2)
- Catenin Alpha 2 (CTNNA2)
- Formin binding protein 1 like (FNBP1L)
- Kinesin Family Member 2A (KIF2A)
- LIM Homeobox 9 (LHX9)
- Sodium Leak Channel, Nonselective (NALCN)
- long intergenic non-protein coding RNA 298 (LINC00298)
- Protein kinase C eta (PRKCH)
- SEL1L adapter subunit of the ERAD E3 ubiquitin ligase (SEL1L)
- Synaptotagmin like 3 (SYTL3)
These genes require biological validation.
The study’s authors concluded that they used a rare variant association study to identify 13 new genes associated with AD. These genes were involved in neuronal development and synaptic integrity rather than innate immunity like the previously published associated genes. These newly identified genes can be potential targets for therapeutic interventions.
Prokopenko D., Morgan SL, Mullin K. et al. Whole genome sequencing reveals new rare variants associated with Alzheimer’s disease in loci related to synaptic function and neuronal development. Alzheimer’s dementia. Published online April 2, 2021. doi: 10.1002 / alz.12319
This article originally appeared on Psychiatry Advisor