Nonreplication in genetic studies of complex diseases - Lessons learned from studies of osteoporosis and tentative remedies

Hui Shen, Yongjun Liu, Pengyuan Liu, Robert R. Recker, Hong Wen Deng

Research output: Contribution to journalReview article

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)365-376
Number of pages12
JournalJournal of Bone and Mineral Research
Volume20
Issue number3
DOIs
StatePublished - Mar 2005

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Osteoporosis
Phenotype
Genetic Heterogeneity
Linkage Disequilibrium
Gene Frequency
Quality Control
Sample Size
Genotype
Population
Genes

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Nonreplication in genetic studies of complex diseases - Lessons learned from studies of osteoporosis and tentative remedies. / Shen, Hui; Liu, Yongjun; Liu, Pengyuan; Recker, Robert R.; Deng, Hong Wen.

In: Journal of Bone and Mineral Research, Vol. 20, No. 3, 03.2005, p. 365-376.

Research output: Contribution to journalReview article

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