Methylation clocks fail to generalize across genetically admixed individuals

Area of Science:

• Genetics
• Epigenetics
• Neuroscience

Background:

• DNA methylation patterns are recognized as potential biomarkers for age-related diseases, including Alzheimer's disease (AD).
• Current methylation clocks have not been thoroughly validated across diverse genetic populations.
• Environmental and social stressors can influence epigenetic aging.

Purpose of the Study:

• To evaluate the accuracy and generalizability of first-, second-, and third-generation DNA methylation clocks.
• To assess the performance of these clocks in genetically diverse cohorts, including African American, Hispanic, and White individuals.
• To investigate the causes of clock inaccuracies in admixed populations.

Main Methods:

• Analysis of DNA methylation data from 621 Alzheimer's disease patients and matched controls.
• Evaluation of methylation clocks in African American, Hispanic, and White cohorts.
• Intersection of clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data.

Main Results:

• Methylation clocks showed decreased accuracy in predicting age in genetically admixed cohorts, particularly those with African ancestry, compared to White cohorts.
• This reduced accuracy was consistent across multiple datasets with European and African ancestry individuals.
• The clocks failed to consistently identify age acceleration in admixed AD cases compared to controls.
• Differential methylation between African and European ancestry individuals was common for clock CpGs.
• While genetic variants rarely disrupted clock CpGs, a significant proportion of clock CpGs had meQTLs with higher frequencies in African genetic ancestries.

Conclusions:

• DNA methylation clocks exhibit limitations in predicting age and Alzheimer's disease risk across diverse populations.
• Differences in genetic and epigenetic patterns between populations contribute to the reduced portability of current methylation clocks.
• Further research is needed to develop more accurate and universally applicable epigenetic aging clocks.