Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Wouter van Rheenen; Aleksey Shatunov; Annelot M Dekker; Russell L McLaughlin; Frank P Diekstra; Sara L Pulit; Rick A A van der Spek; Urmo Võsa; Simone de Jong; Matthew R Robinson; Jian Yang; Isabella Fogh; Perry Tc van Doormaal; Gijs H P Tazelaar; Max Koppers; Anna M Blokhuis; William Sproviero; Ashley R Jones; Kevin P Kenna; Kristel R van Eijk; Oliver Harschnitz; Raymond D Schellevis; William J Brands; Jelena Medic; Androniki Menelaou; Alice Vajda; Nicola Ticozzi; Kuang Lin; Boris Rogelj; Katarina Vrabec; Metka Ravnik-Glavač; Blaž Koritnik; Janez Zidar; Lea Leonardis; Leja Dolenc Grošelj; Stéphanie Millecamps; François Salachas; Vincent Meininger; Mamede de Carvalho; Susana Pinto; Pietro Fratta; Simon Topp; Charles Curtis; Christopher E Shaw; Bradley N Smith; P Nigel Leigh; John Powell; Cathryn M Lewis; Gerome Breen; Ammar Al-Chalabi; PARALS Registry

doi:10.1038/ng.3622

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Wouter van Rheenen, Aleksey Shatunov, Annelot M Dekker, Russell L McLaughlin, Frank P Diekstra, Sara L Pulit, Rick A A van der Spek, Urmo Võsa, Simone de Jong, Matthew R Robinson, Jian Yang, Isabella Fogh, Perry Tc van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, William Sproviero, Ashley R Jones, Kevin P Kenna, Kristel R van EijkOliver Harschnitz, Raymond D Schellevis, William J Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik-Glavač, Blaž Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Pietro Fratta, Simon Topp, Charles Curtis, Christopher E Shaw, Bradley N Smith, P Nigel Leigh, John Powell, Cathryn M Lewis, Gerome Breen, Ammar Al-Chalabi, PARALS Registry

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Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Original language	English
Pages (from-to)	1043–1048
Journal	Nature Genetics
Volume	48
Early online date	25 Jul 2016
DOIs	https://doi.org/10.1038/ng.3622
Publication status	Published - Sept 2016

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van Rheenen, W., Shatunov, A., Dekker, A. M., McLaughlin, R. L., Diekstra, F. P., Pulit, S. L., van der Spek, R. A. A., Võsa, U., de Jong, S., Robinson, M. R., Yang, J., Fogh, I., van Doormaal, P. T., Tazelaar, G. H. P., Koppers, M., Blokhuis, A. M., Sproviero, W., Jones, A. R., Kenna, K. P., ... PARALS Registry (2016). Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics, 48, 1043–1048. https://doi.org/10.1038/ng.3622

@article{58a64d23bb4f4b4f8db973d4abc32187,

title = "Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis",

abstract = "To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.",

author = "{van Rheenen}, Wouter and Aleksey Shatunov and Dekker, {Annelot M} and McLaughlin, {Russell L} and Diekstra, {Frank P} and Pulit, {Sara L} and {van der Spek}, {Rick A A} and Urmo V{\~o}sa and {de Jong}, Simone and Robinson, {Matthew R} and Jian Yang and Isabella Fogh and {van Doormaal}, {Perry Tc} and Tazelaar, {Gijs H P} and Max Koppers and Blokhuis, {Anna M} and William Sproviero and Jones, {Ashley R} and Kenna, {Kevin P} and {van Eijk}, {Kristel R} and Oliver Harschnitz and Schellevis, {Raymond D} and Brands, {William J} and Jelena Medic and Androniki Menelaou and Alice Vajda and Nicola Ticozzi and Kuang Lin and Boris Rogelj and Katarina Vrabec and Metka Ravnik-Glava{\v c} and Bla{\v z} Koritnik and Janez Zidar and Lea Leonardis and Gro{\v s}elj, {Leja Dolenc} and St{\'e}phanie Millecamps and Fran{\c c}ois Salachas and Vincent Meininger and {de Carvalho}, Mamede and Susana Pinto and Pietro Fratta and Simon Topp and Charles Curtis and Shaw, {Christopher E} and Smith, {Bradley N} and Leigh, {P Nigel} and John Powell and Lewis, {Cathryn M} and Gerome Breen and Ammar Al-Chalabi and {PARALS Registry}",

year = "2016",

month = sep,

doi = "10.1038/ng.3622",

language = "English",

volume = "48",

pages = "1043–1048",

journal = "Nature Genetics",

issn = "1061-4036",

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van Rheenen, W, Shatunov, A, Dekker, AM, McLaughlin, RL, Diekstra, FP, Pulit, SL, van der Spek, RAA, Võsa, U, de Jong, S, Robinson, MR, Yang, J, Fogh, I, van Doormaal, PT, Tazelaar, GHP, Koppers, M, Blokhuis, AM, Sproviero, W , Jones, AR, Kenna, KP, van Eijk, KR, Harschnitz, O, Schellevis, RD, Brands, WJ, Medic, J, Menelaou, A, Vajda, A, Ticozzi, N, Lin, K , Rogelj, B, Vrabec, K, Ravnik-Glavač, M, Koritnik, B, Zidar, J, Leonardis, L, Grošelj, LD, Millecamps, S, Salachas, F, Meininger, V, de Carvalho, M, Pinto, S, Fratta, P , Topp, S , Curtis, C , Shaw, CE , Smith, BN , Leigh, PN , Powell, J , Lewis, CM , Breen, G , Al-Chalabi, A & PARALS Registry 2016, 'Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis', Nature Genetics, vol. 48, pp. 1043–1048. https://doi.org/10.1038/ng.3622

TY - JOUR

T1 - Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

AU - van Rheenen, Wouter

AU - Shatunov, Aleksey

AU - Dekker, Annelot M

AU - McLaughlin, Russell L

AU - Diekstra, Frank P

AU - Pulit, Sara L

AU - van der Spek, Rick A A

AU - Võsa, Urmo

AU - de Jong, Simone

AU - Robinson, Matthew R

AU - Yang, Jian

AU - Fogh, Isabella

AU - van Doormaal, Perry Tc

AU - Tazelaar, Gijs H P

AU - Koppers, Max

AU - Blokhuis, Anna M

AU - Sproviero, William

AU - Jones, Ashley R

AU - Kenna, Kevin P

AU - van Eijk, Kristel R

AU - Harschnitz, Oliver

AU - Schellevis, Raymond D

AU - Brands, William J

AU - Medic, Jelena

AU - Menelaou, Androniki

AU - Vajda, Alice

AU - Ticozzi, Nicola

AU - Lin, Kuang

AU - Rogelj, Boris

AU - Vrabec, Katarina

AU - Ravnik-Glavač, Metka

AU - Koritnik, Blaž

AU - Zidar, Janez

AU - Leonardis, Lea

AU - Grošelj, Leja Dolenc

AU - Millecamps, Stéphanie

AU - Salachas, François

AU - Meininger, Vincent

AU - de Carvalho, Mamede

AU - Pinto, Susana

AU - Fratta, Pietro

AU - Topp, Simon

AU - Curtis, Charles

AU - Shaw, Christopher E

AU - Smith, Bradley N

AU - Leigh, P Nigel

AU - Powell, John

AU - Lewis, Cathryn M

AU - Breen, Gerome

AU - Al-Chalabi, Ammar

AU - PARALS Registry

PY - 2016/9

Y1 - 2016/9

N2 - To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

AB - To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

U2 - 10.1038/ng.3622

DO - 10.1038/ng.3622

M3 - Article

C2 - 27455348

SN - 1061-4036

VL - 48

SP - 1043

EP - 1048

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Abstract

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