Summary: A new study reveals a novel genetic risk loci for Alzheimer’s disease. Using single cell gene expression patterns, researchers found genetic changes are expressed in microglia cells. The mutations are associated with an increased risk of Alzheimer’s disease.
Source: UNC Health Care.
A large-scale international study has discovered new genetic risk loci for Alzheimer’s disease, and researchers published their work in Nature Genetics.
Combining genetic data on a large-scale and in a non-conventional manner resulted in the discovery of multiple novel genetic factors and biological mechanisms that contribute to the pathogenesis of the disease. The study was led by Danielle Posthuma from the VU University in Amsterdam, Ole Andreassen from the University of Oslo, and Stephan Ripke from the Broad Institute in Boston, and was carried out as part of an initiative of the Psychiatric Genomics Consortium, which was founded by Patrick Sullivan, MD, Yeargen Distinguished Professor of Psychiatry and Genetics and Director of the Center for Psychiatric Genomics in the UNC School of Medicine. Sullivan is also lead principal investigator for the consortium.
Alzheimer’s disease (AD) is the most common neurodegenerative disease. More than 30 million people are affected worldwide, and this is predicted to double every 20 years, expecting 115.4 million people to be diagnosed with Alzheimer’s by 2050. To improve the current treatment, we require an improved understanding of underlying biological mechanisms that are involved in the initiation of pathological processes leading to clinical Alzheimer’s, which is largely under genetic influence. And so identifying genetic risk factors will increase our insight into this devastating disease.
Genetic defects within the immune system and lipid components
The current study is the largest genetic study of Alzheimer’s so far, including over 455,000 individuals. The study included clinical diagnoses to define the patient group, but also included a group of people where parental Alzheimer’s status was considered. For all individuals, genetic information was available which allowed to scan the genome for possible genetic risk factors. This combined analysis yielded 29 genome-wide significant loci for the disease, including nine novel genetic loci. Results imply that genetic defects in genes involved in the immune system and components associated to lipids, contribute to the Alzheimer’s risk.
“Specifically, using single cell gene expression patterns, we show that genetic changes in genes that are expressed in microglia cells, are associated with increased risk for AD,” Posthuma said. “Microglial cells are an important part of the immune system of the brain. This finding suggests that we should widen our focus to also include microglia models when performing functional research in AD, in addition to the conventional approach of neuronal models.”
Iris Jansen, co-first author of the publication, said: ”We additionally detect genetic changes in proteins that are involved in lipid components. This link has already been described for the APOE gene, the strongest genetic risk factor for AD, but our results show that other lipid proteins might also be genetically affected. This observation strengthens the hypothesis that AD pathogenesis involves an interplay between inflammation and lipids, as lipid changes might harm immune responses of microglia, thereby affecting the vascular health of the brain.”
Indirect genetic effects on Alzheimer’s through cognitive reserve
The study also tested the involvement of any indirect genetic effects on AD risk. In accordance with previous clinical research, which showed a protective effect of cognitive reserve on Alzheimer, the study reports a similar positive effect of cognitive skills on AD, yet this time supported by genetics. “This finding implies that a portion of the genetic risk factors affect cognitive reserve, which subsequently decrease the risk for AD”, said Jeanne Savage, co-first author of the study.
This study of unprecedented size was made possible by using data from various clinical cohorts as well as the UK Biobank.
Source: UNC Health Care
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Original Research: Abstract for “Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk” by Iris E. Jansen, Jeanne E. Savage, Kyoko Watanabe, Julien Bryois, Dylan M. Williams, Stacy Steinberg, Julia Sealock, Ida K. Karlsson, Sara Hägg, Lavinia Athanasiu, Nicola Voyle, Petroula Proitsi, Aree Witoelar, Sven Stringer, Dag Aarsland, Ina S. Almdahl, Fred Andersen, Sverre Bergh, Francesco Bettella, Sigurbjorn Bjornsson, Anne Brækhus, Geir Bråthen, Christiaan de Leeuw, Rahul S. Desikan, Srdjan Djurovic, Logan Dumitrescu, Tormod Fladby, Timothy J. Hohman, Palmi V. Jonsson, Steven J. Kiddle, Arvid Rongve, Ingvild Saltvedt, Sigrid B. Sando, Geir Selbæk, Maryam Shoai, Nathan G. Skene, Jon Snaedal, Eystein Stordal, Ingun D. Ulstein, Yunpeng Wang, Linda R. White, John Hardy, Jens Hjerling-Leffler, Patrick F. Sullivan, Wiesje M. van der Flier, Richard Dobson, Lea K. Davis, Hreinn Stefansson, Kari Stefansson, Nancy L. Pedersen, Stephan Ripke, Ole A. Andreassen & Danielle Posthuma in Nature Genetics. Published January 7 2019.
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.