Figure 3.

Enrichment levels of different qualifying variant categories among the three study-wide significant pulmonary fibrosis genes. We compared enrichment of qualifying variants across increasing minor allele frequency (MAF) and varying in silico effects to assess which variation type was most attributable to pulmonary fibrosis disease risk. (A) Six paired comparisons were done to a single background variation estimate: the percentage of exome-wide ultrarare autosomal synonymous variants that belong to the case subjects (8,279 of 141,449; Ps = 0.0583). (B) Forest plot derived from a multivariate logistic regression assessing the relative contribution of different qualifying variant categories. All categories are mutually exclusive (see Methods section in online supplement). The loss-of-function (LoF) category represents LoF variants with an MAF less than or equal to 0.1%. The LoF category is prematurely truncated for illustrative purposes; however, the effect size and 95% confidence interval (CI) are provided. The missense probably damaging ultrarare category includes variants predicted to be “probably damaging” by Polymorphism Phenotyping version 2 with an MAF less than 0.05% in the test population and absent in Exome Variant Server (EVS) and Exome Aggregation Consortium (ExAC release 0.3.1). The missense probably damaging MAF less than or equal to 0.1% represents variants not in the ultrarare category and that are predicted to be “probably damaging” with a MAF less than or equal to 0.1% across the test population, EVS, and ExAC cohorts. The missense “possibly/benign” category includes missense variants predicted to be “possibly damaging” or “benign” with a MAF less than or equal to 0.1% across the test population, EVS, and ExAC cohorts (including ultrarare possibly/benign missense variants). The “neutral” category represents ultrarare putatively neutral (synonymous) variants across the three pulmonary fibrosis genes (TERT, RTEL1, and PARN). N/A = not applicable; OR = odds ratio.