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Articles   |    
Revisiting Schizophrenia Linkage Data in the NIMH Repository: Reanalysis of Regularized Data Across Multiple Studies
Veronica J. Vieland, Ph.D.; Kimberly A. Walters, Ph.D.; Thomas Lehner, Ph.D.; Marco Azaro, Ph.D.; Kathleen Tobin, Ph.D.; Yungui Huang, Ph.D.; Linda M. Brzustowicz, M.D.
Am J Psychiatry 2014;171:350-359. doi:10.1176/appi.ajp.2013.11121766
View Author and Article Information

Dr. Brzustowicz serves as a consultant for the Janssen Pharmaceutical Companies of Johnson & Johnson. The other authors report no financial relationships with commercial interests.

Supported by NIH grants R01 MH086117 and U24 MH068457.

From the Battelle Center for Mathematical Medicine, Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; the Department of Genetics, Rutgers University, Piscataway, N.J.; and NIMH, Bethesda, Md.

Address correspondence to Dr. Vieland (veronica.vieland@nationwidechildrens.org).

Copyright © 2014 by the American Psychiatric Association

Received December 06, 2011; Revised January 14, 2013; Revised June 02, 2013; Revised August 05, 2013; Accepted August 12, 2013.

Abstract

Objective  The Combined Analysis of Psychiatric Studies (CAPS) project conducted extensive review and regularization across studies of all schizophrenia linkage data available as of 2011 from the National Institute of Mental Health-funded Center for Collaborative Genomic Studies on Mental Disorders, also known as the Human Genetics Initiative (HGI). The authors reanalyzed the data using statistical methods tailored to accumulation of evidence across multiple, potentially highly heterogeneous, sets of data.

Method  Data were subdivided based on contributing study, major population group, and presence or absence within families of schizophrenia with a substantial affective component. The posterior probability of linkage (PPL) statistical framework was used to sequentially update linkage evidence across these data subsets (omnibus results).

Results  While some loci previously implicated using the HGI data were also identified in the present omnibus analysis (2q36.1, 15q23), others were not. Several loci were found that had not previously been reported in the HGI samples but are supported by independent linkage or association studies (3q28, 12q23.1, 11p11.2, Xq26.1). Not surprisingly, differences were seen across population groups. Of particular interest are signals on 11p15.3, 11p11.2, and Xq26.1, for which data from families with a substantial affective component support linkage while data from the remaining families provide evidence against linkage. All three of these loci overlap with loci reported in independent studies of bipolar disorder or mixed bipolar-schizophrenia samples.

Conclusions  Public data repositories provide the opportunity to leverage large multisite data sets for studying complex disorders. Analysis with a statistical method specifically designed for such data enables us to extract new information from an existing data resource.

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FIGURE 1. Omnibus Linkage Results, Including All Population Groups and Families With Either Schizophrenia or Schizophrenia With a Substantial Affective Componenta

a Data from the Human Genetics Initiative. The posterior probability of linkage (PPL) is on the probability scale (0 to 1.0); values <2% (horizontal line) indicate evidence against linkage, while values >2% indicate (some degree of) evidence in favor of linkage.

FIGURE 2. Linkage Results by Population Groupsa

a Data from the Human Genetics Initiative. PPL=posterior probability of linkage.

FIGURE 3. Linkage Results by Clinical Subgroupsa

a Data from the Human Genetics Initiative. PPL=posterior probability of linkage.

FIGURE 4. Linkage Findings for the Combined Analysis of Psychiatric Studies (CAPS) Project and Compared With Original Reportsa

a Thresholds and intervals for inclusion of original signals were taken directly from published reports and generally correspond to “suggestive” linkage. Where intervals were not reported, the average reported interval of 16 cM was imposed. Omnibus posterior probability of linkage (PPL) results are shown above the dotted line. “CAPS For” includes all regions with PPL>10%. This threshold was selected to similarly reflect what might correspond to a “suggestive” level of support. “CAPS Against” includes all regions with PPL<2% (evidence against linkage). Note also that because of the low resolution of genetic scale in this figure, no attempt was made to harmonize the genetic maps across the original reports; different studies reported their results on Rutgers, Marshfield, Genethon, and genetic location database maps.

Anchor for Jump
TABLE 1.Primary Linkage Findings Across Data Subsets (Omnibus) and for Population Groups and Clinical Subgroupsa
Table Footer Note

a Data from the Human Genetics Initiative. Shown here are posterior probabilities of linkage (PPLs) for all loci with PPL>0.25 in at least one subsample. The highest PPL per row is in boldface. By convention, PPLs ≥2% are reported to two decimal places and those <2% to three.

Table Footer Note

b Genetic positions (in centimorgans) refer to hg19 Build 37. When the PPL exceeds 0.25 in multiple subgroups, the position shown is from the omnibus scan if the omnibus PPL >0.25 or for the subgroup with the largest PPL otherwise.

Table Footer Note

c Instances in which a subgroup peak is close to but not directly over the omnibus peak: on chromosome 6, the European American peak is PPL=0.256 at 104 cM; on chromosome 12, African American and schizophrenia peaks at 116 cM are PPL=0.254 and PPL=0.356, respectively.

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