Exome-wide rare variant analysis in familial essential tremor

Area of Science:

• Genetics
• Neurology
• Movement Disorders

Background:

• Essential tremor (ET) is a prevalent, heritable movement disorder with an elusive genetic basis.
• Few susceptibility genes have been identified and replicated for ET.
• Understanding ET genetics is crucial for diagnosis and treatment.

Purpose of the Study:

• To identify novel candidate genes contributing to essential tremor predisposition.
• To utilize whole exome sequencing and association studies to uncover genetic factors in ET.
• To investigate the role of rare deleterious variants in ET etiology.

Main Methods:

• Whole exome sequencing was performed on eight multigenerational families with autosomal-dominant ET.
• Prioritized variants were tested for association in a separate cohort of 521 ET cases and 596 controls.
• Gene-based burden analyses were conducted in an additional dataset of 789 ET patients and 770 controls.

Main Results:

• Fifteen variants co-segregated with ET in families; rs749875462 (CCDC183), rs535864157 (MMP10), and rs114285050 (GPR151) showed nominal association.
• No significant enrichment of rare variants was found within these candidate genes.
• MMP10, involved in inflammatory responses to neuronal damage, was highlighted for further investigation.

Conclusions:

• MMP10 is a promising candidate gene for essential tremor, warranting further genetic and functional studies.
• The study suggests that susceptibility to ET may involve rare deleterious coding variants in numerous genes.
• Future research is necessary to validate identified genes and elucidate their biological mechanisms in ET.