A recent study by NRI researcher Saroja Voruganti and her laboratory highlights the value of genome-wide analysis and underscores the reality that seemingly unrelated diseases often share common, underlying factors. In their recent publication (Chittoor et al., 2016) the researchers identified two genes, ITPR1 and CNTN4, as potential mediators of uric acid concentration. Notably, neither of these genes shows an obvious connection to uric acid, but they have been linked to autism and other neurological disorders.

The Voruganti laboratory is interested in the metabolic processes that lead from nutrients to their end products, specifically uric acid. Hyperuricemia, or elevated levels of serum uric acid (SUA), is linked to diseases including gout, hypertension, and additional cardiometabolic diseases. Hypouricemia, in contrast, has been associated with risk for MS, Parkinson’s and Alzheimer’s disease.

To identify genes and mutations to those genes that affect SUA levels, Dr. Voruganti’s group mines genomic data looking for genetic variants associated with increased or decreased SUA. This data mining often includes analyses known as genome-wide association studies, which identify genetic variation across a population and attempt to associate specific variants with specific disease risks. “Our methods include family-based association studies that are designed to detect associations while accounting for relatedness among individuals,” says lead author Geetha Chittoor. Across the human genome, we can expect to find such variation at a rate of approximately 1 per 300 nucleotides. Some variants are common, occurring in ~40 % of the population, while others are very rare (<0.1% of the population). Still, since the human genome contains 3 billion nucleotide base pairs, we each typically have at least several hundred thousand variations in our genomes which serve, in part, to differentiate one person’s risk for disease from that of another person. Using GWAS, Chittoor et al. found associations with serum uric acid and variants in the genes ITPR1 and CNTN4 in a study cohort of Mexican Americans

Uric acid transport into and out of the kidneys is the primary means by which its serum levels are altered, and the overwhelming majority of genetic variants associated with hyper-/hypouricemia are found in uric acid transporter genes. Hence, it is significant that neither ITPR1 nor CNTN4 code for transporters. In fact, neither is known to directly affect uric acid metabolism or excretion. Rather, both genes are involved in neurodevelopment: mutations in ITPR1 are associated with delayed motor development and mild cognitive impairment in infants (spinocerebellar ataxia), and loss of CNTN4 is associated with autism spectrum disorders and other cognitive defects. “Given the increasing recognition of uric acid’s role in neurodevelopment and cognition,” adds Dr. Voruganti, “this is a very interesting finding.”

Heretofore, serum uric acid levels have not been associated with autism or related disorders. The results from Chittoor et al. indicate that there may be genetic factors common to both SUA regulation and risk for cognitive defects, and further suggest new research directions to determine whether this link is present in other populations and, if so, what the implications are for managing diet to mitigate risk of cognitive disorders.


Chittoor G, Kent JW Jr, Almeida M, Puppala S, Farook VS, Cole SA, Haack K, Göring HH, MacCluer JW, Curran JE, Carless MA, Johnson MP, Moses EK, Almasy L, Mahaney MC, Lehman DM, Duggirala R, Comuzzie AG, Blangero J, Voruganti VS (2016). GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC Genomics. 17:276.