Thirteen new rare candidate loci associated with Alzheimer disease (AD) were identified. These findings 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 loci and regions. An independent cohort of 1669 individuals was used to replicate these findings.

A total of 54,669,406 variants were identified, 2% of which were in protein-coding exons. Most variants were rare (minor allele frequency [MAF] £1%, 77% of variants).


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Using a single-variant approach, a total of 24,301 rare variants associated with AD at a significance of P <.01. No variants reached genome-wide significance, but the top 271 were significant at P <5×104.

The regions of rs74065194 (MAF, 0.0066; P =.011) and rs192471919 (MAF, 0.0054; P =.017) were replicated in the independent cohort and 2 in a meta-analysis (rs147918541: MAF, 0.0072; P =2.44×104; rs141228575/rs147002962: MAF, 0.0069; P =3.3×104).

Using a spatial-clustering approach, 1756 regions associated with AD at a significant of P <.01. No regions reached genome-wide significance, but the top 47 were significant at P <5×104.

In total 4 regions were replicated in the independent cohort (all P £1.79×104) and 6 in a meta-analysis (all P £3.27×105).

Comparing the closest genes identified in the variant and regional analyses identified 90 common genes, which were associated with 152 processes and pathways enriched for positive regulation of nervous development, heart development, sensory organ development, trans-synaptic signaling, and tissue morphogenesis.

The networks associated with these genes comprised 1274 interacting proteins, many of which were established AD genes. The highest ranked gene ontology terms were nervous system development, neurogenesis, and developmental process.

The investigators identified a total of 13 genes which had never been associated with AD previously:

  • APC regulator of WNT signaling pathway (APC)
  • chromosome 15 open reading frame 41 (C15ORF41)
  • C2 domain containing 3 centriole elongation regulator (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, non-selective (NALCN)
  • long intergenic non-protein coding RNA 298 (LINC00298)
  • protein kinase C eta (PRKCH)
  • SEL1L adaptor subunit of ERAD E3 ubiquitin ligase (SEL1L)
  • synaptotagmin like 3 (SYTL3)

These genes require biological validation.

The study authors concluded that they identified 13 novel genes associated with AD using a rare-variant association study. These genes were involved with neuronal development and synaptic integrity and not with innate immunity like the associated genes published previously. These newly identified genes may be potential targets for therapeutic interventions.

Reference

Prokopenko D, Morgan SL, Mullin K, et al. Whole-genome sequencing reveals new Alzheimer’s disease–associated rare variants in loci related to synaptic function and neuronal development. Alzheimer’s Dement. Published online April 2, 2021. doi:10.1002/alz.12319