Based on an extensive search of the literature, we developed a comprehensive list of candidate genes for obesity. Using genome-wide association data from a large consortium meta-analysis, we show nominally significant evidence of enrichment for association among candidate genes compared with non-candidate genes. This enrichment is particularly evident among genes identified from human linkage and association studies, and for genes proposed from at least three separate lines of evidence.
These results suggest that, to a mild extent, candidate genes are more likely to be truly associated than other non-candidate genes, at least for obesity-susceptibility. However, the degree of enrichment is small and the statistical significance in our data is marginal despite the extensive length of the candidate gene list and the large sample size. The fact that candidate genes will have made the list based on evidence of small studies and false-positive observations may have contributed to the limited enrichment, in particular if there was only one source of evidence. Analysis methods can be devised that give more weight to candidate than non-candidate genes, but the relative weighting cannot be high and any improvement in power would be slight. Similarly, focusing exclusively on candidate genes is unlikely to lead to significant gains in power. Since most genes in the genome are not candidate genes, it is likely that much of the unexplained heritability for BMI can be attributed to genes that are not currently considered as candidates.
We considered the regions around genes with no prior evidence for candidacy as a baseline for comparison, rather than intergenic regions. Other authors have presented evidence that SNPs in genes are more strongly associated than those in non-coding regions (6
). We were interested in whether, given a focus on testing genes, there is value in specifically considering candidate genes. Our results suggest that although there is evidence for the enrichment of association in candidate genes for BMI, the minor extent of that enrichment implies limited practical utility for improving the power of association studies.
As a side issue, we considered several possible tests of enrichment and introduced a novel test, the rank tail-strength, which appears to yield the most significant results across a range of tests. It was not the most significant test for any of the analyses we performed, but was nominally or borderline significant in all the cases in which other tests were significant. Given the potentially confusing array of enrichment tests available, the rank tail-strength shows promise as a test with consistent power. Its analytic distribution is known when the number of genes is large, as is the case here, ensuring the type-1 error rate is correct. To more thoroughly characterize its properties, its power should be assessed under a range of simulated conditions. This is beyond the scope of the present work, but our results suggest that further study of this method is warranted.
For the three candidate genes with the strongest associations in GIANT (BDNF, SH2B1, MC4R), there was evidence for their candidacy from multiple sources, whereas the other candidate genes with the next strongest associations only had evidence from one category each, with the exception of CFB. Of interest is that the SNPs in the top four candidate genes were either non-synonymous or in moderately high LD with a non-synonymous SNP.
BMI and related obesity-susceptibility traits are common phenotypes with a modest heritability (h2: ~40–70%) and a non-Mendelian pattern of inheritance. It remains to be determined whether the degree of the enrichment of association in candidate genes can be generalized to similar traits and conditions, and which characteristics (e.g. heritability, prevalence, inheritance pattern) influence the degree of enrichment most. We should also note that we only considered genes for overall obesity-susceptibility, as assessed by BMI, rather than body fat distribution or body shape.
Taken together, we observed evidence for the enrichment of association in candidate genes, suggesting that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus exclusively on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.