Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia

Noa Carrera; Manuel Arrojo; Julio Sanjuán; Ramón Ramos-Ríos; Eduardo Paz; Jose J Suárez-Rama; Mario Páramo; Santiago Agra; Julio Brenlla; Silvia Martínez; Olga Rivero; David A Collier; Aarno Palotie; Sven Cichon; Markus M Nöthen; Marcella Rietschel; Dan Rujescu; Hreinn Stefansson; Stacy Steinberg; Engilbert Sigurdsson; David St Clair; Sarah Tosato; Thomas Werge; Kari Stefansson; Jose Carlos González; Joaquín Valero; Alfonso Gutiérrez-Zotes; Antonio Labad; Lourdes Martorell; Elisabet Vilella; Ángel Carracedo; Javier Costas

doi:10.1016/j.biopsych.2011.09.032

Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia

Noa Carrera, Manuel Arrojo, Julio Sanjuán, Ramón Ramos-Ríos, Eduardo Paz, Jose J Suárez-Rama, Mario Páramo, Santiago Agra, Julio Brenlla, Silvia Martínez, Olga Rivero, David A Collier, Aarno Palotie, Sven Cichon, Markus M Nöthen, Marcella Rietschel, Dan Rujescu, Hreinn Stefansson, Stacy Steinberg, Engilbert SigurdssonDavid St Clair, Sarah Tosato, Thomas Werge, Kari Stefansson, Jose Carlos González, Joaquín Valero, Alfonso Gutiérrez-Zotes, Antonio Labad, Lourdes Martorell, Elisabet Vilella, Ángel Carracedo, Javier Costas

55 Citations (Scopus)

Abstract

Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. The 5 independent nsSNPs with false discovery rate q ≤.25, as well as 13 additional nsSNPs at p <.01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10 ^-6, allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

Original language	English
Journal	Biological Psychiatry
Volume	71
Issue number	2
Pages (from-to)	169-77
Number of pages	9
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2011.09.032
Publication status	Published - 15 Jan 2012

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Carrera, N., Arrojo, M., Sanjuán, J., Ramos-Ríos, R., Paz, E., Suárez-Rama, J. J., Páramo, M., Agra, S., Brenlla, J., Martínez, S., Rivero, O., Collier, D. A., Palotie, A., Cichon, S., Nöthen, M. M., Rietschel, M., Rujescu, D., Stefansson, H., Steinberg, S., ... Costas, J. (2012). Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia. Biological Psychiatry, 71(2), 169-77. https://doi.org/10.1016/j.biopsych.2011.09.032

Carrera, N, Arrojo, M, Sanjuán, J, Ramos-Ríos, R, Paz, E, Suárez-Rama, JJ, Páramo, M, Agra, S, Brenlla, J, Martínez, S, Rivero, O, Collier, DA, Palotie, A, Cichon, S, Nöthen, MM, Rietschel, M, Rujescu, D, Stefansson, H, Steinberg, S, Sigurdsson, E, St Clair, D, Tosato, S, Werge, T, Stefansson, K, González, JC, Valero, J, Gutiérrez-Zotes, A, Labad, A, Martorell, L, Vilella, E, Carracedo, Á & Costas, J 2012, 'Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia', Biological Psychiatry, vol. 71, no. 2, pp. 169-77. https://doi.org/10.1016/j.biopsych.2011.09.032

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abstract = "Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. The 5 independent nsSNPs with false discovery rate q ≤.25, as well as 13 additional nsSNPs at p <.01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10 -6, allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.",

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AU - Carrera, Noa

AU - Arrojo, Manuel

AU - Sanjuán, Julio

AU - Ramos-Ríos, Ramón

AU - Paz, Eduardo

AU - Suárez-Rama, Jose J

AU - Páramo, Mario

AU - Agra, Santiago

AU - Brenlla, Julio

AU - Martínez, Silvia

AU - Rivero, Olga

AU - Collier, David A

AU - Palotie, Aarno

AU - Cichon, Sven

AU - Nöthen, Markus M

AU - Rietschel, Marcella

AU - Rujescu, Dan

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Sigurdsson, Engilbert

AU - St Clair, David

AU - Tosato, Sarah

AU - Werge, Thomas

AU - Stefansson, Kari

AU - González, Jose Carlos

AU - Valero, Joaquín

AU - Gutiérrez-Zotes, Alfonso

AU - Labad, Antonio

AU - Martorell, Lourdes

AU - Vilella, Elisabet

AU - Carracedo, Ángel

AU - Costas, Javier

PY - 2012/1/15

Y1 - 2012/1/15

N2 - Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. The 5 independent nsSNPs with false discovery rate q ≤.25, as well as 13 additional nsSNPs at p <.01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10 -6, allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

AB - Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs). We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures. The 5 independent nsSNPs with false discovery rate q ≤.25, as well as 13 additional nsSNPs at p <.01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10 -6, allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility. Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

U2 - 10.1016/j.biopsych.2011.09.032

DO - 10.1016/j.biopsych.2011.09.032

M3 - Journal article

C2 - 22078303

SN - 0006-3223

VL - 71

SP - 169

EP - 177

JO - Biological Psychiatry

JF - Biological Psychiatry

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ER -

Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia

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