A Haptoglobin (HP) Structural Variant Alters the Effect of <i>APOE</i> Alleles on Alzheimer's Disease

AbstractBackgroundHaptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid-β (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.MethodsHP genotypes were imputed in 29 cohorts from the Alzheimer’s Disease (AD) Genetics Consortium (N=22,651). Associations between the HP polymorphism and AD risk and age of onset through APOE interactions were investigated using regression models.ResultsThe HP polymorphism significantly impacts AD risk and age at onset in European-descent individuals (and in meta-analysis with African Americans) by modifying both the protective effect of APOEε2 and the detrimental effect of APOEε4, especially for APOEε4 carriers.DiscussionThe effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.</jats:sec

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association

Sorting nexin 3 mutation impairs development and neuronal function in Caenorhabditis elegans

The sorting nexins family of proteins (SNXs) plays pleiotropic functions in protein trafficking and intracellular signaling and has been associated with several disorders, namely Alzheimer's disease and Down's syndrome. Despite the growing association of SNXs with neurodegeneration, not much is known about their function in the nervous system. The aim of this work was to use the nematode Caenorhabditis elegans that encodes in its genome eight SNXs orthologs, to dissect the role of distinct SNXs, particularly in the nervous system. By screening the C. elegans SNXs deletion mutants for morphological, developmental and behavioral alterations, we show here that snx-3 gene mutation leads to an array of developmental defects, such as delayed hatching, decreased brood size and life span and reduced body length. Additionally, ∆snx-3 worms present increased susceptibility to osmotic, thermo and oxidative stress and distinct behavioral deficits, namely, a chemotaxis defect which is independent of the described snx-3 role in Wnt secretion. ∆snx-3 animals also display abnormal GABAergic neuronal architecture and wiring and altered AIY interneuron structure. Pan-neuronal expression of C. elegans snx-3 cDNA in the ∆snx-3 mutant is able to rescue its locomotion defects, as well as its chemotaxis toward isoamyl alcohol. Altogether, the present work provides the first in vivo evidence of the SNX-3 role in the nervous system.This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the Project POCI-01- 0145-FEDER-007038; and by a 2016 NARSAD Young Investigator Grant (#24929) from the Brain and Behavior Research Foundation. This work was developed under the scope of the Project NORTE-01- 0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). NV is supported by the FCT Fellowship SFRH/ BPD/91250/2012. AJR is an FCT Investigator IF/00883/2013. CB is supported by a FCT Grant SFRH/BPD/74452/2010 (POPH/FS). PM is supported by a fellowship from the project “Envelhecimento cognitivo saudável–proporcionar saúde mental no processo biológico do envelhecimento” (Contract P-139977) funded by Calouste Gulbenkian– Inovar em Saúde. Research in AXC’s lab is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant agreement 640553-ACTOMYO). AXC has a FCT Investigator position funded by FCT and co-funded by the European Social Fund through Programa Operacional Temático Potencial Type 4.2 promotion of scientifc employment. FC is supported by the FCT fellowship SFRH/BPD/93528/2013.info:eu-repo/semantics/publishedVersio

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness