Recent human evolution has shaped geographical differences in susceptibility to disease.

Area of Science:

• Human genetics
• Population genetics
• Complex disease research

Background:

• Over two decades of research have identified over 51,000 genetic associations with complex diseases.
• Genome-Wide Association Studies (GWAS) have accelerated the discovery of potential disease-risk variants.
• Many identified variants fail replication, leading to concerns about false positives.

Purpose of the Study:

• To investigate global patterns of replicability for published genetic association studies.
• To analyze the relationship between genetic differentiation and disease-associated loci replicability across human populations.

Main Methods:

• Analysis of genetic differentiation across human populations for disease-associated genes.
• Correlation analysis between population genetic differentiation and replicability of disease loci.
• Comparison of allele frequencies in replicated versus non-replicated genes.

Main Results:

• Genes linked to complex diseases exhibit less genetic differentiation among populations than the genome-wide average.
• Replicability differences for disease loci between European and East Asian populations correlate with genetic differentiation.
• Highly replicated genes show higher frequencies of derived alleles in Europeans and Asians compared to Africans.

Conclusions:

• The genetic basis of complex diseases is heterogeneous.
• Recent human evolutionary history influences current disease susceptibility patterns.
• Some associations failing replication may not be false positives but reflect population-specific genetic architectures.