“Are We There Yet?”: Deciding When One Has Demonstrated Specific Genetic Causation in Complex Diseases and Quantitative Traits

Abstract

Although mathematical relationships can be proven by deductive logic, biological relationships can only be inferred from empirical observations. This is a distinct disadvantage for those of us who strive to identify the genes involved in complex diseases and quantitative traits. If causation cannot be proven, however, what does constitute sufficient evidence for causation? The philosopher Karl Popper said, "Our belief in a hypothesis can have no stronger basis than our repeated unsuccessful critical attempts to refute it." We believe that to establish causation, as scientists, we must make a serious attempt to refute our own hypotheses and to eliminate all known sources of bias before association becomes causation. In addition, we suggest that investigators must provide sufficient data and evidence of their unsuccessful efforts to find any confounding biases. In this editorial, we discuss what "causation" means in the context of complex diseases and quantitative traits, and we suggest guidelines for steps that may be taken to address possible confounders of association before polymorphisms may be called "causative."

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee

“…When the data for both sexes were combined, the haplotype frequency in patients (5.2%) was significantly higher than that in controls (3.5%) (OR 1.53, 95% CI 1.02-2. 30). An analysis of pairwise linkage disequilibrium between ASPN 5-SNP haplotypes and the ASPN aspartic acid repeat alleles revealed that specific SNP haplotypes were commonly associated with the 3 most common aspartic acid repeat alleles (Figure 1).…”

“…The strongest evidence for a real connection between a gene and a disease or trait should come from a systematic replication of a statistically significant association, in which any source of bias or inconsistency has been eliminated (30). After several independent groups of investigators replicate a finding, it seems reasonable to conclude with sufficient certainty that a link between a gene and a disease has been demonstrated (31).…”

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

“…51 Attempts to combat this problem often focus on P-values, with the rationale that by choosing the models least likely to be found by random chance alone, the probability of including a false positive will be greatly reduced. 52 Unfortunately, when considering a complex trait, the effect sizes of individual SNPs and pairwise interactions are generally fairly small. This limits the significance level that these models are able to attain in typical epidemiologic studies, which means that true positives may be removed during P-value adjustment.…”

Evidence for Non‐additive Influence of Single Nucleotide Polymorphisms within the Apolipoprotein E Gene

“…A major impediment in studying the contribution of genetic variation to interindividual variation in quantitative levels of apolipoproteins, and other risk factors for developing coronary heart disease, is that the available statistical models are not realistic representations of the biological complexity of genotype-phenotype relationships (Page et al 2003;Sing et al 2003). Phe-nomena such as allelic and genotypic heterogeneity, pleiotropy, gene by environment interaction and gene by gene interaction (epistasis) are realities that cannot easily be modelled, or estimated and tested, using population based samples of human data (Clark, 2000).…”