# Copy Number Variant Duplications Associated with Essential Tremor

## TL;DR

This study finds that rare copy number duplications in protein-coding regions may contribute to the genetic risk of essential tremor, a neurological disorder.

## Contribution

The study identifies rare CNV duplications as potential contributors to essential tremor's missing heritability.

## Key findings

- ET patients showed significantly elevated duplication burden compared to controls in CNV number, length, and genes affected.
- Duplications in brain-expressed and cerebellum-expressed genes were enriched in ET patients.
- Duplications involving ZNF813 were less frequent in ET patients than in controls.

## Abstract

Essential tremor (ET) is a complex neurological disorder with a strong genetic basis, yet there remains a disparity between its estimated heritability and currently known genetic risk. This missing heritability has led to a lack of appropriate treatments and has exacerbated the misdiagnosis of patients.

To address the missing heritability of ET, we called copy number variants (CNVs) in a large cohort of ET patients (n = 1,853) and unaffected controls (n = 10,336). CNVs were called from single nucleotide polymorphism (SNP) microarray data using PennCNV and QuantiSNP and only rare CNVs (frequency < 1%) intersecting protein coding regions of the genome were analyzed. To investigate whether CNV occurrence was associated with ET, global burden, pathogenicity burden, gene set enrichment, and gene burden tests were conducted.

Global duplication burden by CNV number, CNV length, and number of genes affected by CNVs were all significantly elevated in ET patients compared to controls. Across gene-sets, duplications affecting Mendeliome genes, genes highly expressed in the brain, and genes expressed in the cerebellum were significantly enriched in patients compared to controls. Gene-based burden testing indicated that duplications involving ZNF813 were significantly less frequent in ET patients than in controls. No associations with deletion events were observed.

Our results point to rare copy number duplications affecting protein coding regions of the genome as likely contributors to ET genetic risk. However, specific susceptibility genes could not be reliably identified, highlighting the need for larger studies of diverse variant types to clarify the genetic architecture of ET.