Nonreplication in Genetic Studies of Complex Diseases—Lessons Learned From Studies of Osteoporosis and Tentative Remedies

Abstract

Inconsistent results have accumulated in genetic studies of complex diseases/traits over the past decade. Using osteoporosis as an example, we address major potential factors for the nonreplication results and propose some potential remedies.Over the past decade, numerous linkage and association studies have been performed to search for genes predisposing to complex human diseases. However, relatively little success has been achieved, and inconsistent results have accumulated. We argue that those nonreplication results are not unexpected, given the complicated nature of complex diseases and a number of confounding factors. In this article, based on our experience in genetic studies of osteoporosis, we discuss major potential factors for the inconsistent results and propose some potential remedies. We believe that one of the main reasons for this lack of reproducibility is overinterpretation of nominally significant results from studies with insufficient statistical power. We indicate that the power of a study is not only influenced by the sample size, but also by genetic heterogeneity, the extent and degree of linkage disequilibrium (LD) between the markers tested and the causal variants, and the allele frequency differences between them. We also discuss the effects of other confounding factors, including population stratification, phenotype difference, genotype and phenotype quality control, multiple testing, and genuine biological differences. In addition, we note that with low statistical power, even a "replicated" finding is still likely to be a false positive. We believe that with rigorous control of study design and interpretation of different outcomes, inconsistency will be largely reduced, and the chances of successfully revealing genetic components of complex diseases will be greatly improved.

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

“…As is the case for most situations where multiple polymorphisms are involved, the contribution of each polymorphism is likely to be relatively small [97,116]. The polymorphisms that have been reported to associate with aseptic loosening include four genes that encode for proinflammatory cytokines and their antagonists (Table 1).…”

“…More credence should be given to the studies that include a larger number of patients (Table 1). However, sample sizes in the thousands are usually needed to detect associations with moderate effect sizes [97,116]. Thus, even the largest studies on aseptic loosening should therefore be considered preliminary (Table 1).…”

“…In regard to these issues, the largest studies are those from Wilkinson and colleagues [32,33,112] and their odds ratios were adjusted for age, sex, time since primary surgery, and amount of polyethylene wear. An additional important confounder that must be considered in genetic association studies is the degree of genetic heterogeneity within the patient populations [97,116]. In this regard, all but one [30] of the genetic association studies focus exclusively on European whites (Table 1).…”

Subtyping schizophrenia: implications for genetic research

“…27 Extensive heterogeneity is the rule in many common complex disorders, including inflammatory bowel disease, 28 rheumatoid arthritis, 29 and osteoporosis. 30 The obverse phenomenon of pleiotropy, that is, multiple phenotypes arising from one genetic factor, is equally common, for example, in demyelinating peripheral neuropathy or axonal neuropathy with vocal cord paresis caused by mutations in the same GDAP1 gene. 31,32 A range of dissimilar syndromes may be varying expressions of a single genetic defect, such as severe neonatal intestinal obstruction, bronchiectatic lung disease, idiopathic pancreatitis, and male infertility, caused by mutations in the CFTR gene.…”

STrengthening the REporting of Genetic Association Studies (STREGA)—an extension of the STROBE statement

“…For example, some papers suggest that replication of findings should be part of the publication [12,13,16,17,23,26,34,36] whereas others consider this suggestion unnecessary or even unreasonable [21,[40][41][42][43][44]. In many publications, the guidance has focused on genetic association studies of specific diseases [14,15,17,19,22,23,25,26,[31][32][33][34][35][36][37][38]or the design and conduct of genetic association studies [13][14][15]17,19,20,22,23,25,[30][31][32]35,36] rather than on the quality of the reporting.…”