The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes.

paper Cited Public

Authors: Cusanovich, Darren A; Billstrand, Christine; Zhou, Xiang; Chavarria, Claudia; De Leon, Sherryl; Michelini, Katelyn; Pai, Athma A; Ober, Carole; Gilad, Yoav
Year: 2012
Journal: Human molecular genetics
PMID: 22286170
DOI: 10.1093/hmg/dds021
PMCID: PMC3315207

Figure 1.

Study design. We performed a gene expression profiling study (1a) to identify differentially expressed genes between individuals with low and high lymphocyte counts, as well as a GWAS (1b) to identify loci associated with lymphocyte counts. We integrated data from the two studies (2) to identify candidate genes that would have been missed by the GWAS alone. Ultimately, we asked whether these candidate genes are also associated with asthma (3).

Figure 2.

GWAS for lymphocyte count. (A) Manhattan plot displaying the −log10 (P-values) for a GWAS of lymphocyte counts in 462 Hutterites. The top two SNPs are circled. (B) Close-up of the region around the top SNP, rs2746347 (red point), which is located within the first intron of PRKAA2. The estimated recombination rate (based on HapMap data) in the region is also plotted. (C) Close-up of the region around the second most significant SNP, rs881827 (red point), located within an intron of S100B.

Figure 3.

Choice of samples for the gene expression profiling study. A histogram of the distribution of lymphocyte counts (x-axis; the transformed residuals after correcting for age) for all available samples (gray bars) and for the 96 individuals chosen for the gene expression profiling study (red bars).

Figure 4.

Integrating the GWAS and gene expression profiling studies. (A) The median lymphocyte count GWAS P-value (y-axis) for an expanding window of genes is plotted in red. Genes are ordered by the strength of evidence supporting differences in expression level between individuals with low and high lymphocyte counts. The blue curves indicate the confidence interval for median P-values for random sets of genes at each test set size (based on 10 000 permutations). (B) A box plot of the distribution of median lymphocyte count GWAS P-values for random sets of 193 genes (based on 10 000 permutations). The whiskers extend to the 5th and 95th percentile. Black points indicate the observed medians outside this range. The red ‘X’ indicates the median P-value observed for the top 193 differentially expressed genes.

Figure 5.

Integrating results with asthma meta-analyses. Box plots of the distribution of median GABRIEL meta-analysis P-values and median EVE meta-analysis P-value for random sets of 117 genes (based on 10 000 permutations). The whiskers extend to the 5th and 95th percentiles. Black points indicate the observed medians outside this range. For each box plot, the red ‘X’ indicates the median P-value observed for the 117 genes carried forward based on the analysis of association with lymphocyte counts.

#	Section	Preview
20	RESULTS — Integrating results from the GWAS and gene expression data analysis	top 33 genes, the median GWAS P-value of the associated cis eQTL SNPs is 0.28, which is much lower…
21	RESULTS — Integrating results from the GWAS and gene expression data analysis	The evidence for a genetic association with each of these 193 genes individually is weak, as…
22	RESULTS — Integrating results from the GWAS and gene expression data analysis	The list of SNPs that are genetically associated with lymphocyte count and the list of genes whose…
23	RESULTS — Integrating results from a GWAS for asthma	Lymphocyte counts were previously identified as an asthma-associated phenotype in the Hutterites…
24	RESULTS — Integrating results from a GWAS for asthma	To test this hypothesis, we used results from the GABRIEL study, a consortium-based meta-analysis of…
25	RESULTS — Integrating results from a GWAS for asthma	As replication is considered the gold standard in confirming association results, we also sought to…
26	DISCUSSION	Our study was motivated by the observations of ‘missing heritability’ in GWAS for complex human…
27	DISCUSSION	In order to find novel candidate asthma genes, we used a combination of approaches, aimed at…
28	DISCUSSION	We performed our GWAS for lymphocyte counts using a modest sample size (462 individuals). As might…
29	DISCUSSION	We also conducted a gene expression profiling study, using a sample size of 95 individuals, which…
30	DISCUSSION	The results of the independent GWAS and gene expression profiling studies indicate that they are…
31	DISCUSSION	Our rationale was simple: if the ranked lists resulting from the two studies do not reflect true…
32	DISCUSSION	in the inclusion of weakly associated SNPs with both gene expression and lymphocyte count. On the…
33	DISCUSSION	We then extended these results to asthma, the phenotype of primary interest. When we considered the…
34	DISCUSSION	It is of course likely that only a subset of these 117 genes is involved in asthma pathogenesis for…
35	DISCUSSION	Our observations, however, are already informative in the context of previous work. Specifically, we…
36	DISCUSSION	the background, we found a significant 2.2-fold enrichment (9.4%; hypergeometric P = 0.008) of our…
37	DISCUSSION	Several genes on our candidate list may be particularly promising although they may not have…
38	DISCUSSION	chromatin mark (54), is among our candidate genes. Remarkably, hematopoietic stem cells in the bone…
39	DISCUSSION	As a whole, the set of 117 loci is enriched with genes involved in biological functions and pathways…

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