Herve Rhinn

Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

Late-onset Alzheimer’s disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these—including APBA2, FYN, RNF219 and SV2A—encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.

Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

Human age-associated traits, such as cognitive decline, can be highly variable across the population, with some individuals exhibiting traits that are not expected at a given chronological age. Here we present differential aging (Δ-aging), an unbiased method that quantifies individual variability in age-associated phenotypes within a tissue of interest, and apply this approach to the analysis of existing transcriptome-wide cerebral cortex gene expression data from several cohorts totaling 1,904 autopsied human brain samples. We subsequently performed a genome-wide association study and identified the TMEM106B and GRN gene loci, previously associated with frontotemporal dementia, as determinants of Δ-aging in the cerebral cortex with genome-wide significance. TMEM106B risk variants are associated with inflammation, neuronal loss, and cognitive deficits, even in the absence of known brain disease, and their impact is highly selective for the frontal cerebral cortex of older individuals (>65 years). The methodological framework we describe can be broadly applied to the analysis of quantitative traits associated with aging or with other parameters.

Parkinson's disease: Guilt by genetic association

Certain sequence variants of the α-synuclein gene are linked to the risk of Parkinsons disease. An analysis of these variants using gene-editing technology provides a possible explanation for this increased risk. See Letter p.95 Determining how genetic risk variants associated with complex diseases actually contribute to the pathological features of the disease remains a challenge. Non-coding sequences variants have been proposed to act in cis to modulate the expression of disease-linked genes, but it is difficult to test this hypothesis because of the complexity of the diseases linked to these variants. Rudolf Jaenisch and colleagues have developed a genetically controlled system to dissect out the cis-acting effect of allelic variants on the expression of the α-synuclein gene SCNA, which has been linked to Parkinsons disease development.

Retraction Note to: Retraction: Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature12415

Retraction: Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease

This corrects the article DOI: 10.1038/nature12415

Retraction: Integrative genomics identifies APOE [epsi]4 effectors in Alzheimer/'s disease

This corrects the article DOI: 10.1038/nature12415