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Novel Locus for Delirium Risk Identified

Key findings

  • By examining the records of participants in the Massachusetts General Hospital biobank initiative, researchers identified a novel locus for delirium risk that spans multiple genes on chromosome 2
  • The strongest association was with an intronic single nucleotide polymorphism in SLC9A4, a sodium/hydrogen exchange pump being investigated as a regulator of pH in the gut
  • Gut-associated inflammatory response may be a risk factor for delirium
  • Five other loci were found that warrant further investigation

Delirium is a common and costly clinical syndrome, as it is associated with increased length of stay and can exacerbate other issues. It is understood to be complex and multifactorial, and much work has been devoted to uncovering its biological basis. Numerous hypotheses of delirium pathogenesis have been proposed, including direct and indirect effects of inflammatory, neuroendocrine and neurodegenerative mechanisms, but none are in widespread clinical use.

Researchers at the Center for Quantitative Health at Massachusetts General Hospital, led by Thomas H. McCoy, MD, director of research, and Roy H. Perlis, MD, director, conducted the first genome-wide association study to focus on delirium, and they discovered a new locus spanning several genes on chromosome 2. They report the findings in Neurobiology of Aging.

Looking for Genome Associations

As part of the study, the researchers accessed electronic health records on individuals who had been genotyped as part of the Partners Healthcare Biobank initiative at Mass General. The researchers compared 421 individuals whose records contained diagnostic codes for delirium and 5,614 matched control subjects whose records did not contain those codes. Both groups were 60 to 90 years old. To minimize the risk of confounding by ancestry, the sample was limited to individuals of northern European descent.

The researchers found that a single locus on chromosome 2 exceeded a standard genome-wide threshold for association (=1.41e-8). It spanned multiple genes, including two sodium/hydrogen exchange pumps (SLC9A4 and SLC9A2) and three interleukin-related genes: interleukin 1 receptor-like 1 (IL1RL1), interleukin 18 receptor 1 (IL18R1) and interleukin 18 receptor-associated protein (IL18RAP).

Five other loci (two on chromosome 2 and one each on chromosomes 6, 7, 10 and 20) were associated with delirium at a level of < 5e-7, and the researchers say these warrant further investigation.

Although this is the first delirium-focused genome-wide association study, previous research has identified candidate genes for delirium, including apolipoprotein E, SLC6A3 and glutamate receptor ionotropic N-methyl-D-aspartate subtype 3A. In this study, however, there was no robust evidence of an association between delirium and any of those genes.

Key Finding

The strongest association in this study was with SLC9A4, which has been investigated as a regulator of pH in the gut. IL18RAP variants have been associated with celiac disease, and mice that have IL1RL1 knocked out fail to produce proinflammatory cytokines when stimulated.

This association suggests that gut immune function is a risk factor for delirium, the researchers conclude. Although the gut is not emphasized in current delirium research, the potential role of immune response is among the most frequently implicated mechanisms.

The Power of Biobanks

A second conclusion, the authors point out, is that large biobanks can be useful for performing genome-wide association studies of the mechanisms responsible for delirium. They express the hope that other research groups will use biobanks or registries in the same way.

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