ParkinsonCanadaV1, Main, Exploration, bibRecord, 000765

Differential effects of severe vs mild GBA mutations on Parkinson disease

Identifieur interne : 000765 ( Main/Exploration ); précédent : 000764; suivant : 000766

Differential effects of severe vs mild GBA mutations on Parkinson disease

Auteurs : Ziv Gan-Or ; Idan Amshalom ; Laura L. Kilarski ; Anat Bar-Shira ; Mali Gana-Weisz ; Anat Mirelman ; Karen Marder ; Susan Bressman ; Nir Giladi ; Avi Orr-Urtreger

Source :

Neurology [ 0028-3878 ] ; 2015.

RBID : PMC:4351661

English descriptors

KwdEn :
- Aged, Cohort Studies, Female, Glucosylceramidase (genetics), Humans, Jews (genetics), Male, Middle Aged, Mutation (genetics), Parkinson Disease (diagnosis), Parkinson Disease (genetics), Severity of Illness Index.
MESH :
- chemical , genetics : Glucosylceramidase.
- diagnosis : Parkinson Disease.
- genetics : Jews, Mutation, Parkinson Disease.
- Aged, Cohort Studies, Female, Humans, Male, Middle Aged, Severity of Illness Index.

Abstract

Objective:

To better define the genotype-phenotype correlations between the type of GBA (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD).

Methods:

We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder GBA mutations, and conducted a meta-analysis of risk and AAO according to GBA genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results.

Results:

Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe GBA mutation carriers, respectively. The observed frequency of severe GBA mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, p < 0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild GBA mutation carriers and 9.92 and 21.29 for severe GBA mutation carriers (p < 1 × 10⁻⁶ for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild GBA mutation carriers, respectively (p = 4.3 × 10⁻⁵).

Conclusions:

These data demonstrate that mild and severe heterozygous GBA mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351661

DOI: 10.1212/WNL.0000000000001315
PubMed: 25653295
PubMed Central: 4351661

Affiliations:

Le document en format XML

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<author><name sortKey="Gana Weisz, Mali" sort="Gana Weisz, Mali" uniqKey="Gana Weisz M" first="Mali" last="Gana-Weisz">Mali Gana-Weisz</name>
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<author><name sortKey="Giladi, Nir" sort="Giladi, Nir" uniqKey="Giladi N" first="Nir" last="Giladi">Nir Giladi</name>
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<author><name sortKey="Orr Urtreger, Avi" sort="Orr Urtreger, Avi" uniqKey="Orr Urtreger A" first="Avi" last="Orr-Urtreger">Avi Orr-Urtreger</name>
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<front><div type="abstract" xml:lang="en"><sec><title>Objective:</title>
<p>To better define the genotype-phenotype correlations between the type of <italic>GBA</italic>
 (glucosidase, beta, acid) mutation, severe or mild, and the risk and age at onset (AAO), and potential mechanism of Parkinson disease (PD).</p>
</sec>
<sec><title>Methods:</title>
<p>We analyzed 1,000 patients of Ashkenazi-Jewish descent with PD for 7 founder <italic>GBA</italic>
 mutations, and conducted a meta-analysis of risk and AAO according to <italic>GBA</italic>
 genotype (severe or mild mutation). The meta-analysis included 11,453 patients with PD and 14,565 controls from worldwide populations. The statistical analysis was done with and without continuity correction (constant or empirical), considering biases that could potentially affect the results.</p>
</sec>
<sec><title>Results:</title>
<p>Among Ashkenazi-Jewish patients with PD, the odds ratios for PD were 2.2 and 10.3 for mild and severe <italic>GBA</italic>
 mutation carriers, respectively. The observed frequency of severe <italic>GBA</italic>
 mutation carriers among patients with PD was more than 4-fold than expected (4.4% vs 0.9%, respectively, <italic>p</italic>
 < 0.0001, Fisher exact test). In the different models of the meta-analysis, the odds ratios for PD ranged between 2.84 and 4.94 for mild <italic>GBA</italic>
 mutation carriers and 9.92 and 21.29 for severe <italic>GBA</italic>
 mutation carriers (<italic>p</italic>
 < 1 × 10<sup>−6</sup>
 for all analyses). Pooled analysis demonstrated AAO of 53.1 (±11.2) and 58.1 (±10.6) years for severe and mild <italic>GBA</italic>
 mutation carriers, respectively (<italic>p</italic>
 = 4.3 × 10<sup>−5</sup>
).</p>
</sec>
<sec><title>Conclusions:</title>
<p>These data demonstrate that mild and severe heterozygous <italic>GBA</italic>
 mutations differentially affect the risk and the AAO of PD. Our results have important implications for genetic counseling and clinical follow-up.</p>
</sec>
</div>
</front>
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<tree><noCountry><name sortKey="Amshalom, Idan" sort="Amshalom, Idan" uniqKey="Amshalom I" first="Idan" last="Amshalom">Idan Amshalom</name>
<name sortKey="Bar Shira, Anat" sort="Bar Shira, Anat" uniqKey="Bar Shira A" first="Anat" last="Bar-Shira">Anat Bar-Shira</name>
<name sortKey="Bressman, Susan" sort="Bressman, Susan" uniqKey="Bressman S" first="Susan" last="Bressman">Susan Bressman</name>
<name sortKey="Gan Or, Ziv" sort="Gan Or, Ziv" uniqKey="Gan Or Z" first="Ziv" last="Gan-Or">Ziv Gan-Or</name>
<name sortKey="Gana Weisz, Mali" sort="Gana Weisz, Mali" uniqKey="Gana Weisz M" first="Mali" last="Gana-Weisz">Mali Gana-Weisz</name>
<name sortKey="Giladi, Nir" sort="Giladi, Nir" uniqKey="Giladi N" first="Nir" last="Giladi">Nir Giladi</name>
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La maladie de Parkinson au Canada (serveur d'exploration)

Differential effects of severe vs mild GBA mutations on Parkinson disease

Differential effects of severe vs mild GBA mutations on Parkinson disease

Source :

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	La maladie de Parkinson au Canada (serveur d'exploration)
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