Sib-pairs in multifactorial disorders: the sib-similarity problem

Area of Science:

• Genetics and genomics
• Complex disease research
• Human genetics

Background:

• Common disorders are a leading cause of morbidity and mortality.
• Genetic factors contribute to disease susceptibility, as evidenced by familial aggregation.
• Environmental and lifestyle modifications, as well as therapeutic interventions, can manage many common disorders.

Purpose of the Study:

• To review the challenges and limitations in identifying influential genetic loci for common disorders.
• To critically evaluate the success of affected sib-pair (ASP) studies in genetic association research.
• To consider the impact of lacking control groups in genetic studies of familial disease.

Main Methods:

• Review of published literature on genetic studies of common disorders, particularly those employing affected sib-pair designs.
• Analysis of the methodological limitations of existing studies, including the absence of control cohorts.
• Consideration of reasons for limited success and high rates of false positives in genotype-trait association studies.

Main Results:

• Despite significant investment, affected sib-pair studies have yielded limited success in identifying robust genetic loci for common disorders.
• A substantial number of genetic studies have been conducted without adequate control groups.
• Suggestive findings from these studies often result in numerous false positives, hindering progress.

Conclusions:

• The current approaches, particularly the heavy reliance on affected sib-pair studies without controls, may be insufficient for dissecting the genetic architecture of common disorders.
• Methodological improvements, including the incorporation of appropriate control groups, are crucial for advancing genetic research in complex diseases.
• Understanding the reasons for limited success is essential for refining strategies to identify true genetic associations and potential therapeutic targets.