Table 4. Pathways identified by causal reasoning.

Pathway	Correctness p (Bonferroni corrected p)	Enrichment p (Bonferroni corrected p)	No. connections (no. possible connections)	Type of pathway
Angiotensin II −	1.2×10−8 (1.4×10−5)	3.4×10−7(3.8×10−4)	12 (204)	Peptide
Estrogen −	0.001 (>1)	0.002 (>1)	3 (26)	Biological process
Adipocyte differentiation −	0.004 (>1)	0.005 (>1)	4 (76)	Biological process
Triamcinolone acetonide +	0.04 (>1)	0.01 (>1)	3 (94)	Chemical

Causal reasoning [11] uses a large curated database of directed regulatory molecular interactions to identify the most plausible upstream regulators of a gene set with a proposed directionality (eg. down-regulated). We considered the 138 genes identified to contain loss of function mutations. One regulatory pathway (angiotensin II) is significant after correction for multiple testing when considering directionality (Correctness p) as well as when ignoring directionality of regulation (Enrichment p).

The sign (−/+) after the regulator's name indicates the loss (−) or gain (+) of activity required to explain the loss of function mutations.

Enrichment p-value indicates the significance of the number of connections apparent in our data compared to the total number of connections.

Correctness p-value also accounts for the regulatory direction (+/−) and indicates the significance of the hypothesis as a regulator.