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New Rare Disease Risk Loci Uncovered With 23andMe Participant Data

NEW YORK – Investigators from 23andMe and GlaxoSmithKline have delved into direct-to-consumer genetic data for research-consented 23andMe customers to find new genetic contributors for a handful of rare diseases.

Although rare diseases each affect fewer than 200,000 individuals apiece in the US, the sheer number of these conditions — approaching 7,000 so far — make rare diseases collectively common, Suyash Shringarpure, a senior scientist in statistical genetics with 23andMe, explained during a presentation at the American Society of Human Genetics virtual annual meeting on Tuesday.

"An estimated 30 million people are affected by rare diseases in the US," he noted, adding that approved treatments are available for just a small fraction of the rare diseases that make up these diagnoses, on the order of 5 percent.

In an attempt to find new disease culprits and corresponding treatment strategies, the team turned to 23andMe's massive customer set. Of the company's 11 million or so genotyped users, Shringarpure noted that around 80 percent are consented to participate in research, with tens of thousands of client surveys rolling in each day.

The current genome-wide association analyses focused on 33 diseases and involved 1.6 million genotyped 23andMe study participants with relevant self-reported data, the researchers reported, including 19,084 rare disease cases. The results, outlined in a MedRxiv preprint posted in mid-June of this year, reproduced 29 documented rare disease associations with effect sizes similar to those in published GWAS for corresponding conditions.

But the team also uncovered significant associations at five new loci for three of the conditions: Duane retraction syndrome, a developmental eye movement disorder marked by lower-than-usual lateral eye movement capabilities; a benign tumor in the auditory-sensory system known as vestibular schwannoma; and spontaneous pneumothorax, a condition marked by sudden lung collapse.

When the team attempted to replicate the associations with genotypes for nearly 5 million individuals of European ancestry from the UK Biobank effort, it successfully validated associations involving variants at three loci, and saw other more tenuous associations showing the same directional effects at the remaining two loci. Similarly, three of the new loci were more closely linked to the condition in question in a follow-up cross-ancestry analysis that included individuals from non-European backgrounds.

For Duane retraction syndrome, for example, the investigators tracked down two distinct loci with significant ties to the condition: sites in or around the OLIG1 and OLIG2 genes that seem to be required for typical eye development in animal models.

On the other hand, the search for vestibular schwannoma contributors led to significant associations at a locus near two genes implicated in a range of other cancer types, namely CDKN2A and CDKN2B, Shringarpure reported, while spontaneous pneumothorax coincided with variants at three previously unreported risk loci, including two parts of the genome implicated in lung function.

"Our results show that self-reported rare disease data is a viable method for discovering genetic associations for rare diseases," the authors wrote in an abstract accompanying the ASHG presentation. "With increasing sample size and diverse imputation reference panels, we may also be able to study rare diseases more widely in multiple populations and improve our understanding of the trans-ethnic genetic architecture of these diseases."

Based on the results so far, the 23andMe team hopes to do similar GWAS on a broader set of rare diseases as additional participant survey data accumulates, including analyses on conditions such as idiopathic pulmonary fibrosis or systemic sclerosis, to better understand disease biology and uncover potential therapeutic strategies.

"As we discover more and more of these associations, we may be able to find associations which tell us about how specific genes are affecting disease and whether we can develop drugs that act against that disease-causing mechanism," Shringarpure said.

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