A variant in PPP4R3A protects against alzheimer‐related metabolic decline

Abstract

Objectives A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer’s disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability. Methods We performed a genome-wide association study (GWAS) of decline in PCC [18F] FDG PET measured in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (n=606). We then performed follow-up analyses to assess the impact of significant single nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent dataset (n=870). Lastly, we assessed whether significant SNPs influence gene expression using two RNA sequencing (RNA-Seq) datasets (n=210 & n=159). Results We demonstrate a novel genome-wide significant association between rs2273647-T in the gene PPP4R3A and reduced [18F] FDG decline (p= 4.44 × 10−8). In a follow-up analysis using an independent dataset, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p=0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 × 10−15). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level. Interpretations PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies.

Common genetic variation influencing human white matter microstructure

“…On the NHGRI-EBI GWAS catalog 54 , our results tagged many variants that had been implicated with brain structures, including 7 in van der Meer, et al 55 for hippocampal subfield volumes, 7 in Verhaaren, et al 56 for cerebral white matter hyperintensity (WMH) burden, 5 in Vojinovic, et al 57 for lateral ventricular volume, 5 in Rutten-Jacobs, et al 26 for WMH and white matter integrity, 2 in Klein, et al 58 for intracranial volume, 2 in Hibar, et al 59 for subcortical brain region volumes, 2 in Fornage, et al 28 for WMH burden, 1 in Elliott, et al 23 for brain imaging measurements, 1 in Luo, et al 60 for voxel-wise brain imaging measurement, 1 in Hashimoto, et al 61 for superior frontal gyrus grey matter volume, 1 in Ikram, et al 62 for intracranial volume, and 1 in Sprooten, et al 63 for global FA (Supplementary Table 14). When the significance threshold was relaxed to 5 × 10 -8 , we tagged variants reported in more previous studies, such as 2 in Shen, et al 64 for brain imaging measurements, 2 in Chung, et al 65 for hippocampal volume in dementia, 1 in Chen, et al 66 for putamen volume, and 1 in Christopher, et al 67 for posterior cingulate cortex (Supplementary Table 15).…”

Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

“…SERPINB1 rs316341 and SPI1 rs1057233 were associated with CSF Aβ levels (Deming et al, 2017;Huang et al, 2017a). The association between decline in brain glucose metabolism and PPP4R3A rs2273647 was recently reported (Christopher et al, 2017). Three ACE polymorphisms (rs4968782, rs4316, rs4343) were associated with CSF levels of ACE gene product (Kauwe et al, 2014).…”

“…Zinc-finger ZCWPW1 is another gene involved in histone modification and epigenetic regulation (He et al, 2010 ). PPP4R3A rs2273647 showed protective effect in risk for AD (Christopher et al, 2017 ). It encodes a regulatory subunit PPP4R3A of serine/threonine phosphatase (Chowdhury et al, 2008 ).…”

Ppp4r3a deficiency leads to depression-like behaviors in mice by modulating the synthesis of synaptic proteins

“…PPP4R3A deficiency prevented neural stem cells from differentiating, leading to neurogenesis deficits during mouse cortical development (Lyu et al, 2013, Moon et al, 2017. A protective PPP4R3A variant, rs2273647-T, was identified in AD patients that help to slow the onset and progression of AD pathology via reduced glucose uptake by the brain (Christopher et al, 2017). In a previous study, we revealed that PPP4R3A acts as a genetic modifier of spinocerebellar atrophy type 3.…”