Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families

PLOS ONE, Dec 2019

We report analyses of a Brazilian study of early onset schizophrenia (BEOS) families. We genotyped 22 members of 4 families on a linkage SNP array and report here non-parametric linkage analyses using MERLIN® software. We found suggestive evidence for linkage on two chromosomal regions, 13q32 and 11p15.4. A LOD score of 2.71 was observed at 13q32 with a one LOD interval extending from 60.63–92.35 cM. From simulations, this LOD score gave a genome-wide empirical corrected p = 0.33, after accounting for all markers tested. Similarly 11p15.4 showed the same maximum LOD of 2.71 and a narrower one LOD interval of 4–14 cM. Of these, 13q32 has been reported to be linked to schizophrenia by multiple different studies. Thus, our study provides additional supporting evidence for an aetiological role of variants at 13q32 in schizophrenia.

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Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families

et al. (2012) Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families. PLoS ONE 7(12): e52262. doi:10.1371/journal.pone.0052262 Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families Ary Gadelha 0 Vanessa Kiyomi Ota 0 Jose Paya Cano 0 Maria Isabel Melaragno 0 Marilia A. C. Smith 0 Jair de Jesus Mari 0 Rodrigo A. Bressan 0 Sintia Iole Belangero 0 Gerome Breen 0 James Bennett Potash, University of Iowa Hospitals & Clinics, United States of America 0 1 Interdisciplinary Lab of Clinical Neurosciences (LiNC), and Schizophrenia Program (PROESQ), Department of Psychiatry, Universidade Federal de Sao Paulo (UNIFESP), Sa o Paulo, Brazil, 2 Morphology and Genetics Department, Universidade Federal de Sao Paulo (UNIFESP) , Sa o Paulo, Brazil, 3 Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London , London , United Kingdom , 4 National Institute of Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, King's College London , London , United Kingdom We report analyses of a Brazilian study of early onset schizophrenia (BEOS) families. We genotyped 22 members of 4 families on a linkage SNP array and report here non-parametric linkage analyses using MERLINH software. We found suggestive evidence for linkage on two chromosomal regions, 13q32 and 11p15.4. A LOD score of 2.71 was observed at 13q32 with a one LOD interval extending from 60.63-92.35 cM. From simulations, this LOD score gave a genome-wide empirical corrected p = 0.33, after accounting for all markers tested. Similarly 11p15.4 showed the same maximum LOD of 2.71 and a narrower one LOD interval of 4-14 cM. Of these, 13q32 has been reported to be linked to schizophrenia by multiple different studies. Thus, our study provides additional supporting evidence for an aetiological role of variants at 13q32 in schizophrenia. - Funding: This study was funded by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (grant number 2011/00030-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Schizophrenia is a chronic, highly disabling disease that has a point prevalence estimate of ,0.5% general population, which usually leads to persistent functional impairment with considerable morbidity and economic cost [1,2]. It is considered a complex trait resulting from both genetic and shared environmental etiological influences. Several studies support a familial aggregation (as reviewed by Sullivan [3]) with a 10-fold increase in risk to sibling of one proband and up to a 40-fold increase when both parents are affected [4]. The genetic contribution to risk is high and heritability estimates based on clinical ascertainment are usually given as over 80% [5,6]. A recent population-based study of 2 million families in Sweden put the estimate at a lower, but still considerable, 64.3%, with a 95% Confidence Interval (C.I.) estimate of 61?7%67?5% [7]. Linkage analysis is a standard approach for identifying the location of genes that cause genetic diseases [8], whose primary advantage lies in detecting genes of moderate to major effect. This contrasts with genome-wide association studies, which are superior at finding loci of small effect [9]. Linkage studies conducted in schizophrenia have yielded positive findings in many different regions of the genome, with a somewhat confusing mixture of replication and non-replication. There is clear heterogeneity with no hard replication for any region, with none being implicated in more than 20% independent studies [3]. Several reasons may explain these results, including locus and phenotypic heterogeneity, inadequate sample size, differences in ascertainment, marker sets, ancestry and statistical methods [10]. A systematic genome-scan meta-analysis [11] found 20 regions that achieved genome-wide linkage evidence. In a recent update of their meta-analysis that included 32 genome-wide SCZ studies, 10 regions were identified, with a concordant finding for the two meta-analysis on chromosome 2q (118.7152 Mb) [10]. More specifically, they found that 10 genome bins are likely to contain loci linked to SCZ, including regions of chromosomes 1q, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, they reported suggestive evidence for linkage on chromosome 8p. Other loci have been reported and replicated in two regions of chromosome 13, one in the region of 13q2133, (, 95 Mb) and another in the 13q1314 region (, 40 Mb) [1217]. In the present study we perform a pilot linkage study in Brazilian families with early-onset schizophrenia in Sao Paulo, Brazil. We report here the (...truncated)


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Ary Gadelha, Vanessa Kiyomi Ota, Jose Paya Cano, Maria Isabel Melaragno, Marilia A. C. Smith, Jair de Jesus Mari, Rodrigo A. Bressan, Sintia Iole Belangero, Gerome Breen. Linkage Replication for Chromosomal Region 13q32 in Schizophrenia: Evidence from a Brazilian Pilot Study on Early Onset Schizophrenia Families, PLOS ONE, 2012, 12, DOI: 10.1371/journal.pone.0052262