Copy Number Variant Duplications Associated with Essential Tremor

BackgroundEssential tremor (ET) is a complex neurological disorder with a strong genetic basis, yet there remains a disparity between the estimated heritability and the currently known genetic risk of ET. This missing heritability of ET has led to a lack of appropriate treatments and has exacerbated the misdiagnosis of patients. MethodsTo 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 retained for analysis. To investigate whether CNV occurrence was associated with ET, analyses were conducted on global burden, pathogenicity burden, gene set enrichment, and gene burden. ResultsGlobal duplication burden by number of CNVs (OR = 1.71 [1.30-2.23], p = 9.8x10-5), CNV length (OR = 1.08 [1.02-1.15], p = 7.1x10-3), and number of genes affected by CNVs (OR = 1.11 [1.05-1.18], p = 5.8x10-4) were all significantly elevated in ET patients compared to controls. Duplications sized 100kbs-500kbs largely explained these associations (number of CNVs: OR = 2.14 [1.54-2.94], p = 3.95x10-6; number of genes: OR = 1.15 [1.06-1.23], p = 3.8x10-4). Across gene-sets, duplications affecting Mendeliome genes (OR = 2.01 [1.36-2.91], p = 3.4x10-4), genes highly expressed in the brain (OR = 1.80 [1.27-2.46], p = 5.06x10-4), and genes expressed in the cerebellum (OR = 1.16 [1.06-1.27], p = 7.31x10-4) were significantly enriched for CNVs in ET patients compared to controls. Finally, gene-based burden testing indicated that duplications involving ZNF813 were significantly less frequent in ET patients than in controls (OR = 0.0411 [0.0026-0.66], p = 2.22x10-5). No associations with deletion events were observed. ConclusionsOur results point to rare copy number duplications mapping to 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 further studies to clarify the genetic architecture of ET.