Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

Benjamin Gaastra; Aleksey Shatunov; Sara Pulit; Ashley R. Jones; William Sproviero; Alexandra Gillett; Zhongbo Chen; Janine Kirby; Isabella Fogh; John F. Powell; P. Nigel Leigh; Karen E. Morrison; Pamela J. Shaw; Christopher E. Shaw; Leonard H. van den Berg; Jan H. Veldink; Cathryn M. Lewis; Ammar Al-Chalabi

doi:10.1080/21678421.2016.1213852

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

Benjamin Gaastra, Aleksey Shatunov, Sara Pulit, Ashley R. Jones, William Sproviero, Alexandra Gillett, Zhongbo Chen, Janine Kirby, Isabella Fogh, John F. Powell, P. Nigel Leigh, Karen E. Morrison, Pamela J. Shaw, Christopher E. Shaw, Leonard H. van den Berg, Jan H. Veldink, Cathryn M. Lewis, Ammar Al-Chalabi

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Abstract

Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10(-3)). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.

Original language	English
Pages (from-to)	593-599
Number of pages	7
Journal	Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume	17
Issue number	7-8
Early online date	1 Sept 2016
DOIs	https://doi.org/10.1080/21678421.2016.1213852
Publication status	Published - 2 Sept 2016

Keywords

Adaptor Proteins, Signal Transducing
Amyotrophic Lateral Sclerosis
Cohort Studies
Cytoskeletal Proteins
Databases, Bibliographic
Female
Genotype
Humans
Male
Middle Aged
Nerve Tissue Proteins
Polymorphism, Single Nucleotide
Receptor, EphA4
Survival Analysis
Time Factors
United Kingdom
Journal Article

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Rare genetic variation_GAASTRA_Accepted13June2016_GOLD VoRFinal published version, 645 KBLicence: CC BY

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Gaastra, B., Shatunov, A., Pulit, S., Jones, A. R., Sproviero, W., Gillett, A., Chen, Z., Kirby, J., Fogh, I., Powell, J. F., Leigh, P. N., Morrison, K. E., Shaw, P. J., Shaw, C. E., van den Berg, L. H., Veldink, J. H., Lewis, C. M., & Al-Chalabi, A. (2016). Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration , 17(7-8), 593-599. https://doi.org/10.1080/21678421.2016.1213852

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title = "Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis",

abstract = "Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10(-3)). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.",

keywords = "Adaptor Proteins, Signal Transducing, Amyotrophic Lateral Sclerosis, Cohort Studies, Cytoskeletal Proteins, Databases, Bibliographic, Female, Genotype, Humans, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptor, EphA4, Survival Analysis, Time Factors, United Kingdom, Journal Article",

author = "Benjamin Gaastra and Aleksey Shatunov and Sara Pulit and Jones, {Ashley R.} and William Sproviero and Alexandra Gillett and Zhongbo Chen and Janine Kirby and Isabella Fogh and Powell, {John F.} and Leigh, {P. Nigel} and Morrison, {Karen E.} and Shaw, {Pamela J.} and Shaw, {Christopher E.} and {van den Berg}, {Leonard H.} and Veldink, {Jan H.} and Lewis, {Cathryn M.} and Ammar Al-Chalabi",

note = "doi: 10.1080/21678421.2016.1213852",

year = "2016",

month = sep,

day = "2",

doi = "10.1080/21678421.2016.1213852",

language = "English",

volume = "17",

pages = "593--599",

journal = "Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration ",

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Gaastra, B, Shatunov, A, Pulit, S, Jones, AR , Sproviero, W , Gillett, A, Chen, Z, Kirby, J, Fogh, I , Powell, JF , Leigh, PN, Morrison, KE, Shaw, PJ, Shaw, CE, van den Berg, LH, Veldink, JH, Lewis, CM & Al-Chalabi, A 2016, 'Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration , vol. 17, no. 7-8, pp. 593-599. https://doi.org/10.1080/21678421.2016.1213852

TY - JOUR

T1 - Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

AU - Gaastra, Benjamin

AU - Shatunov, Aleksey

AU - Pulit, Sara

AU - Jones, Ashley R.

AU - Sproviero, William

AU - Gillett, Alexandra

AU - Chen, Zhongbo

AU - Kirby, Janine

AU - Fogh, Isabella

AU - Powell, John F.

AU - Leigh, P. Nigel

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Shaw, Christopher E.

AU - van den Berg, Leonard H.

AU - Veldink, Jan H.

AU - Lewis, Cathryn M.

AU - Al-Chalabi, Ammar

N1 - doi: 10.1080/21678421.2016.1213852

PY - 2016/9/2

Y1 - 2016/9/2

N2 - Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10(-3)). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.

AB - Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10(-3)). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.

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KW - Amyotrophic Lateral Sclerosis

KW - Cohort Studies

KW - Cytoskeletal Proteins

KW - Databases, Bibliographic

KW - Female

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Nerve Tissue Proteins

KW - Polymorphism, Single Nucleotide

KW - Receptor, EphA4

KW - Survival Analysis

KW - Time Factors

KW - United Kingdom

KW - Journal Article

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U2 - 10.1080/21678421.2016.1213852

DO - 10.1080/21678421.2016.1213852

M3 - Article

C2 - 27584932

SN - 2167-8421

VL - 17

SP - 593

EP - 599

JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

IS - 7-8

ER -

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

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Keywords

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