Editors' ChoiceHuman Genetics

Dark Matter Revealed

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Science Translational Medicine  30 Jun 2010:
Vol. 2, Issue 38, pp. 38ec103
DOI: 10.1126/scitranslmed.3001403

Over the last 3 years, genome-wide association studies (GWAS) have revealed hundreds of genetic loci that are associated with susceptibility to over 100 complex traits and diseases. The magnitude of the risk conferred by these common variants has been modest, leaving much of the heritability of these diseases and traits unexplained. Accounting for this missing heritability, otherwise known as “dark matter”—a term coined by National Institutes of Health director Francis Collins—will be essential before we can move toward personalizing medicine on the basis of an individual’s genetic makeup. Now, Surolia and colleagues successfully demonstrate through candidate gene resequencing that rare variants may be a source of this missing heritability in diseases of autoimmunity.

Because of recent data demonstrating that mice in which sialic acid acetylesterase (SIAE) was knocked out spontaneously developed autoantibodies, the authors performed complete resequencing of this gene in over 900 individuals with autoimmune conditions, including diabetes, lupus, rheumatoid arthritis, and inflammatory bowel disease (IBD). They then compared their results with those obtained from over 600 healthy controls. Remarkably, they discovered that 27 of the 923 patients (2.9%) with autoimmune disorders carried rare mutations in SIAE that resulted in a dysfunctional protein. In contrast, only 2 of 648 (0.3%) healthy controls carried similar gene mutations. Thus, the carriers of the SIAE variant in this study harbored a dramatic eightfold increase in risk for autoimmune conditions. In an interesting related finding, recent studies on activated B cells from patients with IBD have shown enhanced abundance of cell-surface sialic acid residues in heterozygote SIAE variant carriers as compared with that of normal controls. Such increased expression of sialic acid could potentially lead to reduced self tolerance and enhanced autoimmunity. Going forward, these data will need to be validated through well-designed prospective genomic studies before any definitive conclusions on the role of SIAE in autoimmunity can be derived. Nevertheless, this study demonstrates a powerful approach to illuminating the “dark matter” of some of society's most common, troubling, and heritable illnesses.

I. Surolia et al., Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 16 June 2010 (10.1038/nature09115). [Abstract]

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