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.
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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)