Genome-wide estimates of heritability and genetic correlations in Essential Tremor

Abstract

Despite considerable efforts to identify disease-causing and risk factors contributing to essential tremor (ET), no comprehensive assessment of heritable risk has been performed to date. We use GREML-LDMS to estimate narrow-sense heritability due to additive effects (h 2 ) and GREMLd to calculate non-additive heritability due to dominance variance (δ 2 ) using data from 1,748 ET cases and 5,302 controls. We evaluate heritability per 10Mb segments across the genome and assess the impact of Parkinson's disease (PD) misdiagnosis on heritability estimates. We apply genetic risk score (GRS) from PD and restless legs syndrome (RLS) to explore its contribution to ET risk and further assess genetic correlations with 832 traits by Linkage disequilibrium score regression. Our results show for the first time that ET is a highly heritable condition (h 2 =0.755, s.e=0.075) in which additive common variability plays a prominent role. In contrast, dominance variance shows insignificant effect on the overall estimates. Heritability split by 10Mb regions revealed increased estimates at chromosomes 6 and 21 suggesting that these may contain causative risk variants influencing susceptibility to ET. The proportion of genetic variance due to PD misdiagnosed cases was estimated to be 5.33%. PD and RLS GRS were not significantly predictive of ET case-control status demonstrating that despite overlapping symptomatology, ET does not seem to share genetic etiologies with PD or RLS. Our study suggests that most of ET genetic component is yet to be discovered and future GWAS will reveal additional risk factors that will improve our understanding of this disabling disorder.

Propranolol significantly reduced DNA polymerase β expression in patients with essential tremor

“…The disease has clinical similarities with some diseases such as dystonia and Parkinson's disease (PD) and can also be seen together with other neurological diseases such as restless leg syndrome. (19,20) Coexistence with other diseases causes difficulties in the diagnosis of ET.…”

“…According to twin studies, the inheritance of ET has been reported to be between 45% and 90%. (20,21) The genetic structure of ET is quite complex. The genetic etiology of ET comprises both monogenic and multifactorial inheritance.…”