<i>TYK2</i> protein-coding variants identified by exon-sequencing of RA cases and controls.

<p>Using dense genotyping, we demonstrate that three <i>TYK2</i> protein-coding variants predicted to be damaging, P1104A, A928V, and I684S, protect against RA (highlighted in red). By exon-sequencing in 1,118 RA cases and 1,118 controls, we identified 23 additional missense variants predicted to be damaging (PolyPhen-2 and SIFT), with no strong evidence of association to RA in gene-based association tests. The <i>TYK2</i> coding exons, the protein domains, and the minor allele count (MAC) of the rare variants (MAC<5) in cases and controls are shown.</p

Results from stepwise conditional analysis of the <i>TYK2</i> locus.

<p>We fine-mapped the <i>TYK2</i> locus using Immunochip data available for 7,222 ACPA+ RA cases and 15,870 controls (MAF>0). (A) In the meta-analysis, the best signal of association was at the <i>TYK2</i> missense variant P1104A (rs34536443).(B) Conditional on P1104A, the best signal of association was at the <i>TYK2</i> missense variant A928V (rs35018800). (C) Conditional on P1104A and A928V variants, the best signal of association is at the <i>TYK2</i> missense variant I684S (rs12720356). (D) Conditional on the 3 RA-protective variants in <i>TYK2</i>, we observed no additional signal of association at the locus (best signal is rs3176768, P = 0.01). P-values from meta-analyses of logistic regressions results from 6 Immunochip collections are shown. The three <i>TYK2</i> missense variants predicted to be damaging and independently associated with RA risk are highlighted in green.</p