Associating complex traits with genetic variants: polygenic risk scores, pleiotropy and endophenotypes

Area of Science:

• Genetics
• Bioinformatics
• Statistical genomics

Background:

• Genotype-phenotype causal modeling has evolved significantly from early designs.
• Genomewide assays have expanded the scope of genotype-phenotype research for complex traits.
• Polygenic risk scores are developed from causal variant clusters to predict clinical diagnoses.

Purpose of the Study:

• To review the evolution and current state of genotype-phenotype causal modeling.
• To discuss challenges and complexities in genomewide investigations.
• To examine controversies and contributing factors in genotype-phenotype research.

Main Methods:

• Review of historical genotype-phenotype causal modeling designs.
• Analysis of genomewide assay applications for complex traits.
• Examination of statistical complexities and research design challenges.

Main Results:

• Genomewide assays have increased the scope of genotype-phenotype research.
• Challenges in research design and statistical complexity hinder prediction reliability.
• Controversies exist regarding heritability estimates and causal clusters.

Conclusions:

• Genotype-phenotype causal modeling faces significant challenges despite advancements.
• Reliability and validity of predictions from genomewide studies require further investigation.
• Pleiotropy and endophenotypes add complexity to causal models.