Genome-wide estimates of heritability and genetic correlations in essential tremor

Monica Diez-Fairen; Sara Bandres-Ciga; Gabrielle Houle; Mike A Nalls; Simon L Girard; Patrick A Dion; Cornelis Blauwendraat; Andrew B Singleton; Guy A Rouleau; Pau Pastor

doi:10.1016/j.parkreldis.2019.05.002

Genome-wide estimates of heritability and genetic correlations in essential tremor

Parkinsonism Relat Disord. 2019 Jul:64:262-267. doi: 10.1016/j.parkreldis.2019.05.002. Epub 2019 May 4.

Authors

Affiliations

¹ Fundació Docència i Recerca Mútua Terrassa, University Hospital Mútua de Terrassa, Terrassa, 08221, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, 08222, Barcelona, Spain.
² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892, MD, USA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18016, Spain.
³ Department of Human Genetics, McGill University, Montréal, H3A 2B4, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, H3A 2B4, Quebec, Canada.
⁴ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892, MD, USA; Data Tecnica International, Glen Echo, 20892, Bethesda, MD, USA.
⁵ Centre Intersectoriel en Santé Durable, Université du Québec, Chicoutimi, G7H 2B1, Quebec, Canada.
⁶ Department of Human Genetics, McGill University, Montréal, H3A 2B4, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, H3A 2B4, Quebec, Canada.
⁷ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892, MD, USA.
⁸ Montreal Neurological Institute, McGill University, Montréal, H3A 2B4, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, H3A 2B4, Quebec, Canada.
⁹ Fundació Docència i Recerca Mútua Terrassa, University Hospital Mútua de Terrassa, Terrassa, 08221, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, 08222, Barcelona, Spain. Electronic address: pastorpau@gmail.com.

Abstract

Introduction: 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.

Methods: We use GREML-LDMS to estimate narrow-sense heritability due to additive effects (h²) and GREMLd to calculate non-additive heritability due to dominance variance (δ²) using data from 1,751 ET cases and 5,311 controls. We evaluate heritability per 10 Mb 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.

Results: We estimated ET narrow-sense heritability to be h² = 75.5% (s.e = ±0.075). In contrast, dominance variance showed insignificant effect on the overall estimates. Heritability split by 10 Mb regions revealed increased estimates at chromosomes 6 and 21. 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.

Conclusions: We show for the first time that ET is a highly heritable condition in which additive common variability plays a prominent role. Chromosomes 6 and 21 may contain causative risk variants influencing susceptibility to ET. 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 contributing to ET.

Keywords: Common variability; Essential tremor; GWAS; Genetic risk scores; Heritability.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Chromosomes, Human, Pair 21 / genetics
Chromosomes, Human, Pair 6 / genetics
Cohort Studies
Diagnostic Errors
Essential Tremor / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study*
Humans
Male
Middle Aged
Parkinson Disease / diagnosis
Parkinson Disease / genetics
Restless Legs Syndrome / genetics

Abstract

Publication types

MeSH terms

Grants and funding