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Biomedical subjects

Philippe Amouyel

Publications and source records attributed to Philippe Amouyel.

3 recordsLinked to original sources

Genome-wide association meta-analysis of eating behavior traits revealed one susceptibility locus for emotional eating.

In order to identify new and genome-wide significant loci for eating behavior traits (cognitive restraint, uncontrolled eating and emotional eating), we conducted a meta-GWAS with seven studies of European ancestry (n&#x2009;=&#x2009;11,250). Eating behavior was assessed using the Three-Factor Eating Questionnaire. Genotype effects of single studies were estimated using additive models adjusting for age, sex, BMI, and principal components and single study results were combined by fixed-effect meta-analysis.For cognitive restraint and uncontrolled eating, no genome-wide significant association could be detected. For emotional eating, one genomic region on chromosome 5 comprising two polymorphisms attained genome-wide significance (P&#x2009;=&#x2009;4.0&#xd7;10-8 for rs6877636 and P&#x2009;=&#x2009;3.2&#xd7;10-8 for rs6897090). The minor alleles were associated with higher emotional eating scores (&#x3b2;=0.093&#x2009;&#xb1;&#x2009;0.017), with a similar direction of effect in each study. Both SNPs, in near perfect linkage disequilibrium, mapped to RP11-24P24.1, a processed pseudogene of ornithine decarboxylase 1 (ODC1). Enrichment analysis revealed a significant overlap between genome-wide BMI-associated variants and nominal emotional eating variants, supporting the hypothesis that shared genetic factors may influence both eating behavior traits and obesity risk. Finally, we observed a number of interesting associations reaching suggestive significance (P&#x2009;<&#x2009;10-6) involving BMI candidate genes, including a suggestive association between FTO variants and cognitive restraint (rs9922708, &#x3b2;&#x2009;=&#x2009;0.069, P&#x2009;=&#x2009;5.9&#xd7;10-7).In conclusion, our meta-GWAS identified for the first time a robust chromosomal region associated with emotional eating in seven studies. Given that emotional eating strongly influences body weight but is often stigmatized, recognizing genetic susceptibility to certain eating behaviors may help reduce stigma and alleviate guilt.

Journal Article

PLCG2 downregulation impairs synaptic function and increases Alzheimer's disease hallmarks in neuronal cultures.

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-&#x3b2; (A&#x3b2;) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLC&#x3b3;2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLC&#x3b3;2 downregulation could increase AD risk by impairing synaptic functions and by increasing A&#x3b2; levels and Tau phosphorylation in neurons.

Alzheimer Disease

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer&#x2019;s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied &#x2018;domain mapping of disease mutations&#x2019; for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64&#x2009;years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8&#x2013;10&#x2009;years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans