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Exome-based Association Study Fleshes Out Coding Variants Contributing to Psoriasis Risk

NEW YORK (GenomeWeb News) – Low-frequency variants in protein-coding portions of the genome may make relatively modest contributions to psoriasis risk, according to an exome sequencing-based association study appearing online yesterday in Nature Genetics.

An international team led by investigators in China did exome sequencing on nearly 1,500 Han Chinese individuals with or without psoriasis, before sifting through those protein-coding sequences to look for non-synonymous variants over-represented in those with the chronic skin condition.

Based on apparent associations from that analysis — together with information on genes implicated in other immune-related conditions in the past — the team then turned to targeted sequencing to assess samples from more than 9,900 other psoriasis patients and nearly as many controls.

The search led to a handful of coding sites with ties to psoriasis, the team reported. But only two of the verified associations involved lower frequency variants: missense changes affecting the interleukin receptor immune IL23R and the gap junction gene GJB2. Rare, missense alterations in two more genes — FUT2 and TARBP1 — showed more tenuous ties to psoriasis.

"Although we did not identify any low-frequency or rare coding variants with strong genetic effect, the data helps us to refine several known GWAS loci and identify some candidate casual variants," co-first author Xin Jin, a researcher affiliated with BGI-Shenzhen and the South China University of Technology, said in a statement.

"It remains to be shown whether limited contribution of rare coding variants will also hold true for other regions outside the target and in other common diseases beyond psoriasis," Jin said.

Past studies have detected dozens of loci that seem to dial up psoriasis risk, Jin and his colleagues noted. But more research is needed to pick out coding variants that are causal to the condition, they noted, and to tease apart contributions by relatively low frequency and rare variants.

To that end, the researchers began by doing an exome sequencing-based association analysis involving 781 individuals from the Han Chinese population with psoriasis and 676 unaffected controls.

Using Illumina's HiSeq 2000 instrument, they sequenced coding regions nabbed from each individual's genome with NimbleGen sequence capture arrays.

Those exome sequences contained a slew of non-synonymous variants, the team found, including 133 single nucleotide changes outside of major histocompatibility complex regions with potential psoriasis associations.

When they focused in at the gene level on coding sequences containing more non-synonymous changes than usual in individuals with psoriasis, meanwhile, the investigators tracked down 742 candidate genes.

For the follow-up phases of the study, the group relied on samples from 9,946 psoriasis patients and 9,906 unaffected control individuals, again from the Chinese population.

In those cases and controls, researchers did targeted sequencing on 1,326 genes: the set of 742 candidates unearthed in their initial gene-focused analysis, along with 622 genes already linked to other immune-related diseases. They also sequenced sites containing the 133 suspicious variants found in the discovery stage of the study, in an effort to verify those associations.

All told, the team saw significant ties to psoriasis for a handful of non-synonymous coding variants. Five were common missense changes affecting the LCE3D, ERAP1, CARD14, and ZNF816A genes.

Just two low-frequency variants — missense changes to IL23R and GJB2 — had statistically significant links to the conditions, researchers reported, while findings from the analysis pointed to suggestive associations for rare missense alterations in the FUT2 and TARBP1 genes.

Likewise, the group noted that non-synonymous single-base changes in the genes selected based on ties to other immune conditions make relatively modest contributions to psoriasis risk.

Moreover, while the work uncovered some similarities between psoriasis risk in the Han Chinese individuals and Europeans profiled in the past, the study's authors also saw potential population-specific differences in the genetics of the disease.