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Rare Late-Onset Alzheimer's Disease Risk Variant Discovered in Icelanders

NEW YORK (GenomeWeb) – An international team of researchers has uncovered a rare variant associated with late-onset Alzheimer's disease.

Through an exome-wide association analysis that drew on nearly 1,400 Alzheimer's disease cases and more than 8,000 controls, the researchers linked a rare variant in the TM2D3 gene to the condition, as they reported today in PLOS Genetics. That variant, they noted, is more common — though still rare — among people of Icelandic descent. Additionally, through functional studies in fruit flies, the researchers found that it likely disrupts Notch signaling.

The Notch pathway, first author Johanna Jakobsdottir from the Icelandic Heart Association noted in a statement, has already been linked to Alzheimer's disease as Notch signaling factors are involved in amyloid plaque pathology — beta-amyloid plaques, along with neurofibrillary tangles, are hallmarks of the disease.

"However, we have not proven causality and further study is needed," she added , "including additional experiments in the fly, DNA sequencing to identify additional variants, and RNA sequencing to study effects on gene expression."

Jakobsdottir and her colleagues combined exome-wide genotyping array data from four population-based cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium to conduct an exome-wide association analysis of 1,383 late-onset Alzheimer's disease cases and 8,141 controls. This analysis highlighted single-nucleotide variants in three genes: APOE, SKAP2, and TM2D3.

APOE, they noted, is a known, important genetic determinant of Alzheimer's disease susceptibility, while the rs17154402 locus in SKAP2 that they linked to the disease had an inconsistent direction of effect in the researchers' initial and follow-up analyses.

The P115L missense variant in TM2D3, meanwhile, didn't exceed the threshold for exome-wide significance. But as the researchers noted that it was enriched among the Icelandic population cohort, significantly associated with Alzheimer's disease within that cohort, and had been linked in previous work to Alzheimer's disease-related biology, they elected to examine it further.

They reported that the P115L variant fully accounted for the association of TM2D3 with Alzheimer's disease, and in a follow-up cohort of 290 cases and 1,529 controls, all from Iceland, they confirmed its link to the disease.

The TM2D3 gene encodes a predicted double-pass transmembrane protein that appears to be evolutionarily conserved, the researchers noted. Though PolyPhen suggested that the P115L variant isn't strongly damaging, it does fall within a well-conserved domain. As proline is often associated with structural kinks, the researchers said that the protein's structure might be affected when proline is exchanged for leucine, which is more common among interior alpha helical structures.

In a series of studies in Drosophila, the researchers turned to the homologous fly gene amx. When amx is mutated, it leads to a maternal effect neurogenic phenotype, which the researchers said is characteristic of defective Notch signaling, and is an embryonic lethal defect.

In their fly studies, the researchers humanized the homologous fly amx gene, replacing it with the human TM2D3 gene, to find that it could substitute for the fly version. When it was added as a construct to flies with mutant amx, the human version, under endogenous amx regulatory sequences, could rescue the mutant phenotype. A construct with a human TM2D3 gene with the P115L variant, meanwhile, could not rescue the mutant fly, indicating that that variant leads to a loss of function in the context of embryonic Notch signaling.

"We have found a rare variant in the TM2D3 gene that correlates with risk of late‐onset Alzheimer's disease and showed that it likely interferes with the Notch signaling pathway, which has relevance for Alzheimer's disease," Jakobsdottir noted.