Exome-wide rare variant analysis in familial essential tremor

Abstract

Introduction: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing.

Methods: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes.

Results: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders.

Conclusions: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

Keywords: Essential tremor; Genetic risk; MMP10; Rare variants; WES.

Figure 1.. Pedigrees for the families that underwent WES, asterisk indicates the family members sequenced.

Genetic pedigrees plots of the eight families (A-H) included in the study are shown. The generation in each pedigree is indicated by roman numerals. The proband is indicated by an arrow. Red asterisk indicates those subjects that were exome sequenced (N=40). Below each pedigree, age at enrollment, age at tremor onset (for cases, if known), tremor region and severity are shown in a table. Tremor region (localization of the tremor): Head (H), Tongue (T), Chin (C), Upper limbs (UL), Lower limbs (LL). Tremor severity corresponds to scores in the Part A of the more affected body region according to the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) [41]. Shading legend: Symbols completely black indicate individuals with clinical definite ET diagnosis; Symbols half vertical black fill indicate individuals with unclear ET diagnosis; Symbols completely blank indicate unaffected individuals; Symbols with a diagonal line indicated deceased relatives. Segregation within families for the three candidate variants (rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050) is also shown in families A, F and H.

Figure 1.. Pedigrees for the families that underwent WES, asterisk indicates the family members sequenced.

Genetic pedigrees plots of the eight families (A-H) included in the study are shown. The generation in each pedigree is indicated by roman numerals. The proband is indicated by an arrow. Red asterisk indicates those subjects that were exome sequenced (N=40). Below each pedigree, age at enrollment, age at tremor onset (for cases, if known), tremor region and severity are shown in a table. Tremor region (localization of the tremor): Head (H), Tongue (T), Chin (C), Upper limbs (UL), Lower limbs (LL). Tremor severity corresponds to scores in the Part A of the more affected body region according to the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) [41]. Shading legend: Symbols completely black indicate individuals with clinical definite ET diagnosis; Symbols half vertical black fill indicate individuals with unclear ET diagnosis; Symbols completely blank indicate unaffected individuals; Symbols with a diagonal line indicated deceased relatives. Segregation within families for the three candidate variants (rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050) is also shown in families A, F and H.

Figure 1.. Pedigrees for the families that underwent WES, asterisk indicates the family members sequenced.

Genetic pedigrees plots of the eight families (A-H) included in the study are shown. The generation in each pedigree is indicated by roman numerals. The proband is indicated by an arrow. Red asterisk indicates those subjects that were exome sequenced (N=40). Below each pedigree, age at enrollment, age at tremor onset (for cases, if known), tremor region and severity are shown in a table. Tremor region (localization of the tremor): Head (H), Tongue (T), Chin (C), Upper limbs (UL), Lower limbs (LL). Tremor severity corresponds to scores in the Part A of the more affected body region according to the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) [41]. Shading legend: Symbols completely black indicate individuals with clinical definite ET diagnosis; Symbols half vertical black fill indicate individuals with unclear ET diagnosis; Symbols completely blank indicate unaffected individuals; Symbols with a diagonal line indicated deceased relatives. Segregation within families for the three candidate variants (rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050) is also shown in families A, F and H.

Figure 1.. Pedigrees for the families that underwent WES, asterisk indicates the family members sequenced.

Genetic pedigrees plots of the eight families (A-H) included in the study are shown. The generation in each pedigree is indicated by roman numerals. The proband is indicated by an arrow. Red asterisk indicates those subjects that were exome sequenced (N=40). Below each pedigree, age at enrollment, age at tremor onset (for cases, if known), tremor region and severity are shown in a table. Tremor region (localization of the tremor): Head (H), Tongue (T), Chin (C), Upper limbs (UL), Lower limbs (LL). Tremor severity corresponds to scores in the Part A of the more affected body region according to the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) [41]. Shading legend: Symbols completely black indicate individuals with clinical definite ET diagnosis; Symbols half vertical black fill indicate individuals with unclear ET diagnosis; Symbols completely blank indicate unaffected individuals; Symbols with a diagonal line indicated deceased relatives. Segregation within families for the three candidate variants (rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050) is also shown in families A, F and H.

Figure 1.. Pedigrees for the families that underwent WES, asterisk indicates the family members sequenced.

Genetic pedigrees plots of the eight families (A-H) included in the study are shown. The generation in each pedigree is indicated by roman numerals. The proband is indicated by an arrow. Red asterisk indicates those subjects that were exome sequenced (N=40). Below each pedigree, age at enrollment, age at tremor onset (for cases, if known), tremor region and severity are shown in a table. Tremor region (localization of the tremor): Head (H), Tongue (T), Chin (C), Upper limbs (UL), Lower limbs (LL). Tremor severity corresponds to scores in the Part A of the more affected body region according to the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) [41]. Shading legend: Symbols completely black indicate individuals with clinical definite ET diagnosis; Symbols half vertical black fill indicate individuals with unclear ET diagnosis; Symbols completely blank indicate unaffected individuals; Symbols with a diagonal line indicated deceased relatives. Segregation within families for the three candidate variants (rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050) is also shown in families A, F and H.