Rare genetic variants impact muscle strength.

Area of Science:

• Genetics
• Human Physiology
• Molecular Biology

Background:

• Muscle strength is a key health indicator, highly heritable, and predicts mortality.
• Understanding the genetic basis of muscle strength is crucial for health and disease prevention.

Purpose of the Study:

• To investigate the association between rare protein-coding genetic variants and hand grip strength.
• To identify genes influencing muscle strength and explore genetic relationships with disease.
• To uncover shared mechanisms between brain and muscle function.

Main Methods:

• Conducted an exome-wide burden association study for rare protein-truncating and damaging missense variants.
• Analyzed data from 340,319 individuals for hand grip strength.
• Investigated the titin (TTN) locus for convergence of rare and common variant signals.

Main Results:

• Identified a significant association between the burden of rare variants and reduced hand grip strength.
• Discovered six significant genes for hand grip strength: KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, and EIF3J.
• Demonstrated convergence of rare and common variant signals at the TTN locus, linking reduced strength to disease.

Conclusions:

• Rare genetic variation significantly impacts muscle strength, with implications for health and mortality.
• Identified key genes and shared mechanisms underlying muscle function, highlighting brain-muscle connections.
• Revealed additive effects of rare and common genetic variations on muscle strength.