Rare variants create synthetic genome-wide associations

Area of Science:

• Human genetics
• Statistical genetics
• Genomic epidemiology

Background:

• Genome-wide association studies (GWAS) have identified thousands of common variants linked to diseases.
• The prevailing hypothesis is that these common variants tag nearby causal sites.
• This has driven extensive resequencing efforts to find these causal variants.

Purpose of the Study:

• To propose and investigate synthetic associations as an alternative explanation for GWAS findings.
• To explore how uncommon or rare variants can create associations attributed to common variants.
• To provide a framework for recognizing and interpreting synthetic associations in GWAS.

Main Methods:

• Computer simulations were used to model the emergence of synthetic associations under various genetic conditions.
• Analysis of real-world datasets, including hearing loss and sickle cell anemia, to demonstrate synthetic association patterns.
• Examination of the extent and characteristics of synthetic associations in known disease datasets.

Main Results:

• Synthetic associations, driven by rare variants, are shown to be an inevitable outcome under plausible genetic models.
• These synthetic associations can significantly contribute to or entirely explain many identified GWAS signals.
• Rare causal mutations for hearing loss and sickle cell anemia were demonstrated to create significant synthetic associations, some spanning large genomic regions.

Conclusions:

• Uncommon and rare genetic variants can readily generate synthetic associations, leading to misattribution to common variants.
• The possibility of synthetic associations necessitates careful consideration during the interpretation and follow-up of GWAS results.
• This phenomenon requires a re-evaluation of strategies for identifying causal variants and understanding disease genetics.