Genome-wide association studies reveal whether genetic variants influence susceptibility to disease, but say nothing about how they do it. In Alzheimer's, for example, most GWAS hits fall in non-coding regions of the genome, suggesting they alter the expression of nearby genes—but which ones and in what cells? Given the role of inflammation in neurodegenerative and other diseases, scientists led by Christophe Benoist, Harvard Medical School, Boston, Barbara Stranger, University of Chicago, and Philip De Jager, Brigham and Women’s Hospital, Boston, wondered how disease-associated genetic variants affect the immune system. As reported in the May 2 Science, they found that genetic variants previously tied to autoimmune diseases more likely influence gene expression in T cells, while other variants linked to neurodegeneration affect gene regulation in monocytes. The results imply that the adaptive and innate arms of the immune system contribute to a different extent to autoimmunity and neurodegeneration, respectively.
“The paper demonstrates the importance of looking in a cell-type-specific way at regulatory networks that are at play in disease,” Eric Schadt, Mount Sinai Hospital, New York, wrote to Alzforum in an email.
Genetic variants that fall in non-coding regions of the genome and influence the expression of genes are called expression quantitative trait loci, or eQTLs. Scientists can find eQTLs by linking the expression of individual genes across a population to genetic variation. Many eQTLs are cell-specific, since a polymorphism may influence expression of genes that are expressed in muscle, for example, but not in other cell types. De Jager and colleagues asked if eQTLs are unique among different cells of the immune system, and how that might relate to disease.
First author Towfique Raj and colleagues isolated immune cells from the blood of 461 young, healthy people aged 18 to 50 of either African-American, East Asian-American, or European-American descent, all living in Boston. The researchers purified both T cells and monocytes, representing the adaptive and innate immune systems, respectively. In each cell type, the researchers measured the expression of genes across the entire genome and then looked for SNPs that could explain any spikes or troughs in expression. In this way, they ferretted out thousands of eQTLs. They then compared these with genetic variants that had been linked to a range of diseases, including various cancers, autoimmune disorders, and neurological and neurodegenerative conditions.
The identified eQTLs largely matched up among the three ancestral groups. However, 37 percent of eQTLs differed between the cell types. Intriguingly, those unique to T cells included single-nucleotide polymorphisms that had been previously linked to autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. By contrast, many eQTLs that were specific to monocytes had been pinpointed as risk factors for neurodegenerative disease such as Alzheimer’s (AD) and Parkinson’s diseases. These included variants near ABCA7, MS4A4A, and CD33 for AD, and LRRK2 and SNCA for PD, all of which were identified in genome-wide association studies.
The findings support the idea that monocytes and related immune cells in the brain, such as microglia and macrophages, are key players in AD (see May 2013 Webinar). What’s more, this study suggests that innate immune factors play a role early in disease, since all the subjects in this study were young and healthy. De Jager said his group is now measuring expression of these genes in monocytes of older people at different points along the trajectory of AD.
Based on previous evidence, the separate influences of the two arms of the immune system on autoimmune versus neurodegenerative disease makes perfect sense, said Richard Ransohoff, Cleveland Clinic, Ohio. “To have it demonstrated this rigorously is exciting,” he said. He agreed that the study also provides potential insight into some of the earliest changes in disease. “This study gives us possible clues to how some of the pathological process might begin, and that may help us find early events that can be modified,” he said. It would be interesting to see how the eQTLs of other immune cells compare to the two examined in this study, he added.
Schadt noted, as did the authors, that the immune cells used for this research did not come from disease-specific tissue, leaving open the possibility that a different eQTL profile might emerge in monocytes from a brain affected by a neurodegenerative disease such as Alzheimer's. Schadt also pointed out that the number of disease-associated eQTLs shared by T cells and monocytes suggests both arms of the immune system may influence susceptibility to some diseases, even if one dominates.
Monica Carson, University of California, Riverside, complimented the approach of contrasting naïve T cells and short-lived monocyte populations because gene expression in neither would have been influenced by the history of the donor. She pointed out that monocytes are precursors to macrophages that infiltrate the brain, suggesting that fundamental genetic susceptibilities in monocytes could underlie Alzheimer’s and other neurodegenerative diseases. “It drives home that the innate immune system and the myeloid cell population are fundamentally important to this disease,” she told Alzforum.—Gwyneth Dickey Zakaib
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- Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, Feng T, Lee M, Asinovski N, Frohlich I, Imboywa S, Von Korff A, Okada Y, Patsopoulos NA, Davis S, McCabe C, Paik HI, Srivastava GP, Raychaudhuri S, Hafler DA, Koller D, Regev A, Hacohen N, Mathis D, Benoist C, Stranger BE, De Jager PL. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014 May 2;344(6183):519-23. PubMed.