Schizophrenia Bulletin vol. 40 no. 1 pp.

6065, 2014
doi:10.1093/schbul/sbt122
Advance Access publication August 22, 2013

Molecular Validation of the Schizophrenia Spectrum

T. BernardBigdeli1, Silviu-AlinBacanu1, Bradley T.Webb1, DermotWalsh2, F. AnthonyONeill3, Ayman H.Fanous1,4,

Brien P.Riley1,5, and Kenneth S.Kendler*,1,5

*To whom correspondence should be addressed; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics of
VCU, Box 980126, Richmond, VA 23298-0126, US; tel: (804)-828-8590, fax: (804)-828-1471, e-mail: kendler@vcu.edu

Background: Early descriptive work and controlled family

and adoption studies support the hypothesis that a range
of personality and nonschizophrenic psychotic disorders
aggregate in families of schizophrenic probands. Can we
validate, using molecular polygene scores from genomewide association studies (GWAS), this schizophrenia spectrum? Methods: The predictive value of polygenic findings
reported by the Psychiatric GWAS Consortium (PGC)
was applied to 4 groups of relatives from the Irish Study of
High-Density Schizophrenia Families (ISHDSF; N = 836)
differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for
affected and unaffected relatives were used to construct perindividual polygene risk scores based on the PGC stage-I
results. We compared mean polygene scores in the ISHDSF
with mean scores in ethnically matched population controls
(N = 929). Results: The schizophrenia polygene score differed significantly across diagnostic categories and was
highest in those with narrow schizophrenia spectrum, lowest
in those with no psychiatric illness, and in-between in those
classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected
subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control
sample. Conclusions: In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous
liability distribution and validates, using aggregate common
risk alleles, a genetic basis for the schizophrenia spectrum
disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk
variants compared with the general population.

Both Kraepelin and Bleuler in their classic descriptions

of, respectively, dementia praecox1 and schizophrenia,2
observed that close relatives of individuals with schizophrenia have excess rates of unusual personalities, features of which appeared to be mild versions of many of
the symptoms seen in their more clearly affected relative.3
Kraepelin noted many eccentric personalities in the
families of his patients with dementia praecox and considered it likely that they suffered from a latent version
of the same principle malady.1(p234) Bleuler articulated a
similar view as follows:
If one observes the relatives of our patients [with schizophrenia], one finds in them peculiarities which are qualitatively
identical with those of the patients themselves, so that the
[patients] disease appears to be only a quantitative increase
of the anomalies seen in the parents and siblings.2(p238)

In the first series of systematic family studies of schizophrenia conducted in Kraepelins Psychiatric Research
Institute early in the 20th century, it was already noted
that a range of disorders other than classical schizophrenia aggregated in relatives including atypical psychoses
and schizoidia or schizoid personality.4 In his very
large classical family study of schizophrenia published in
1938, Kallmann articulated what he alternatively called
the group of schizoform abnormalities or the schizophrenic disease-complex.5
The modern concept of the schizophrenia spectrum
derives from the Danish Adoption Study of Schizophrenia6,7
where biological relatives of schizophrenic adoptees
were shown to be at increased risk both for classical
schizophrenia as well as milder syndromes, alternatively
called latent, borderline, or uncertain schizophrenia.8
Interviews from this study were used to develop the
diagnostic category of schizotypal personality disorder in
DSM-III.9

Key words: schizophrenia/schizophrenia spectrum/

polygene score/GWAS

The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oup.com

60

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

1
Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA; 2Health Research Board, Dublin,
Ireland; 3Centre for Public Health, Queens University, Belfast, UK; 4Mental Health Service Line, Washington VA Medical Center,
Washington, DC; 5Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

Molecular Validation of the Schizophrenia Spectrum

While schizophrenia and psychotic affective illness could

be clearly assigned to the two extremes of the schizophrenia spectrum, the proper ordering of schizoaffective disorder, schizotypal/paranoid personality disorder, and
other nonaffective psychoses could not be unambiguously
determined.16(p749)

Attempts to verify the schizophrenia spectrum using

molecular tools have been more limited. One notable
effort utilized linkage in the Irish Study of High-Density
Schizophrenia Families (ISHDSF).17 Genome-wide,
limit of detection (LOD) scores for schizotypy in nonpsychotic members of these families were significantly
correlated with LOD scores of schizophrenia in all pedigree members,18 suggesting a sharing of at least some risk
variants across the schizophrenia spectrum. Two studies
have found that a variant in the risk gene ZNF804A
which has been shown in several studies to alter liability
to schizophrenia19,20is also associated with schizotypal
personality traits.21,22
Technological advances have now permitted another
look at the question of the genetic relationship between
disorders within the schizophrenia spectrum. Using
genome-wide association studies (GWAS), polygene
scores can be statistically constructed that reflect a broad
array of measured molecular variants that in aggregate
predispose to illness, typically to high levels of statistical significance, but accounting for small overall proportions of variance.23 In this report, we examine polygene
scores for schizophrenia based on GWAS in members
of the ISHDSF. Our prediction is that these scores will
be highest in members of these pedigrees with classical
schizophrenia, lower in members affected with other disorders in the putative schizophrenia spectrum, and lowest
in unaffected members of these pedigrees. In addition, we
predict that even the unaffected members of these pedigreeschosen to contain at least two individuals with
schizophrenia or poor-outcome schizoaffective disorder

(PO-SAD)will have elevated polygene scores for schizophrenia compared with a control sample.
Methods
Subjects and Single Nucleotide Polymorphism
Genotyping
Irish Study of High Density Schizophrenia Families.
Fieldwork for the ISHDSF was conducted between April
1987 and November 1992, with probands ascertained
from public psychiatric hospitals in Ireland and Northern
Ireland with local ethics approval.17 Selection criteria were
two or more first-degree relatives meeting DSM-III-R criteria for schizophrenia or PO-SAD. Diagnoses were based
on the Structured Interview for DSM-III-R Diagnosis24
and the Structured Interview for Schizotypy.25 Relatives
suspected of psychotic illness were always interviewed by
trained psychiatrists, and trained social workers would
typically interview other relatives. Hospital and/or outpatient records were obtained and abstracted in over 98%
of cases with schizophrenia or SAD diagnoses. Family
history diagnoses on first-degree relatives by the Family
History-Research Diagnostic Criteria (FH-RDC) instrument26 were also routinely obtained.
Independent review of all pertinent diagnostic information (interview, hospital abstract, and family history reports) was made blind to pedigree assignment
and marker genotypes by K.S.K. and D.W., with each
diagnostician making up to 3 best-estimate DSM-III-R
diagnoses. Agreement between the 2 diagnosticians was
high (weighted =0.94 0.05). Our diagnostic schema
included 10 categories ranked by the degree to which they
reflected the core vs periphery of the schizophrenia spectrum based on our review of prior family and adoption
studies and, in particular, the Roscommon Family Study
done by the same research team in the same country
using similar diagnostic procedures. For most subsequent
analyses, these 10 categories were divided into 4 groups:
(1) narrowschizophrenia, PO-SAD, and simple schizophrenia; (2) intermediateschizotypal personality disorder, schizophreniform and delusional disorders, atypical
psychosis, and good-outcome SAD; (3) broadpsychotic
affective illness and paranoid, avoidant, and schizoid personality disorder; and (4) very broadany other psychiatric illness, particularly nonpsychotic major depression,
anxiety disorders, and alcohol dependence. The sample
included, of course, individuals who received no lifetime
diagnosis of psychiatric illness.
In total, 853 individuals representing 237 pedigrees were
selected from the ISHDSF for high-throughput genotyping
on the Illumina 610-Quad platform (at Illumina, Inc),
and genotypes were called with the BeadStudio software
package (Illumina, Inc). Initial exclusion criteria for
samples was call rate below 95%. Exclusion criteria for
single nucleotide polymorphisms (SNPs) were as follows:
third allele observed; pseudoautosomal or mitochondrial;
61

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

Several modern family studies as well as a diagnostic

re-review of the Danish Adoption Study findings using
operationalized diagnostic criteria and blind diagnosis
verified the genetic/familial association between schizophrenia and both personality disorders (especially schizotypal and paranoid) and nonschizophrenic psychotic
disorders, especially schizoaffective disorder and atypical
psychosis.1015
In the most systematic effort to clarify the nature of
the schizophrenia spectrum, Kendler and colleagues
applied a multiple threshold model to results from the
Roscommon Family Study.16 The model postulated positions on a single dimension of genetic/familial liability
for the key diagnostic categories in the following order:
schizophrenia, schizoaffective disorder, schizotypal/paranoid personality disorder, other nonaffective psychoses,
and psychotic affective illness. This model fit the family
data well but the article concluded:

T. B.Bigdeli etal

Population-Based Controls. Details of recruitment,

screening, and quality control (QC) methods employed in
the Wellcome Trust Case Control Consortium (WTCCC)
2 have been published elsewhere.28 Controls (N = 2048)
were ascertained with written informed consent from the
Irish GeneBank and represented blood donors from the
Irish Blood Transfusion Service recruited in the Republic
of Ireland. All controls were of Irish origin (born of Irish
parents and having all 4 grandparents born in Ireland or
the UK) but were not specifically screened for psychiatric illness. Individuals taking regular prescribed medication were excluded from blood donation in Ireland, and
donors were not financially remunerated. Meaningful
misclassification bias is unlikely because the lifetime
prevalence of schizophrenia is relatively low (<1%), and
affected individuals typically chronically take medication
and probably have a reduced likelihood of volunteering
for blood donations. Following QC, the control sample
included 1794 participants.
All samples were genotyped using the Affymetrix 6.0
platform totaling 893 634 autosomal SNPs, either at
the Affymetrix or Broad Institute laboratories. A subset of samples (N = 37) was genotyped at both sites and
successfully identified as duplicates as part of the QC
procedure. For all samples passing laboratory QC, raw
intensities (from the.CEL files) were renormalized within
collections using CelQuantileNorm (see http://outmodedbonsai.sourceforge.net/). Genotype-calling was performed by GoldenHelix, Inc, utilizing BeagleCall29 in an
iterative procedure that used normalized genotypes and
genotype probabilities generated by BirdSeed (see http://
www.broadinstitute.org/mpg/birdsuiCte/birdseed.html)
as inputs. Only those individual genotypes with genotype probability of at least 0.97 were retained. Exclusion
criteria for SNPs were as follows: third allele observed;
pseudoautosomal, mitochondrial, or X/Y; MAF
<1%; call rate <97%; and P < 1 106 for deviations
from Hardy-Weinberg equilibrium. A total of 686 646
62

autosomal SNPs were available for analysis; genotyping

completion was greater than 99.9%.
To assess relatedness among study individuals, we
examined estimates of genetic relatedness (identityby-descent) generated using PLINK27 for unrelated
sample pairs with allele-sharing greater than 5%; samples involved in more than one such relationship were
excluded outright, else one sample in a pair was excluded
at random. Given the potential of genotyping site effects
to manifest in an aggregate score (data not shown), we
elected to include in our final analysis only those controls
genotyped at the Affymetrix site (N=929).
Genome-Wide Imputation
Phasing of entire chromosomes or chromosome arms was
performed using SHAPEIT.30 Genotype imputation of
additional SNPs was carried out with IMPUTE2 v.2.031
using the March 2012 release (v3) of the 1000 Genomes
Project data (www.1000genomes.org).32 Imputation
analysis was performed for genomic windows of 5 Mb
with an overlap interval of 500 Kb between adjacent segments. Following the recommendations of the authors of
IMPUTE2, we did not limit our imputation procedure to
European reference samples.33 SNPs were filtered using
an information threshold of 0.5 and only those imputed
genotypes with a corresponding probability of at least
.95 were retained. Phasing, imputation, and postprocessing were performed independently for the ISHDSF and
WTCCC samples. Within each study, monomorphic sites
were excluded, as well as any SNP that yielded at least
one Mendelian inconsistency.
Construction of PolygeneScore
We constructed a polygene score based on results from the
discovery phase (N = 21856) of the Psychiatric GWAS
Consortium (PGC) of SCZ.34 SNPs present on Illumina
610-Quad or imputed successfully (information >.5;
MAF 2% in N = 286 independent ISHDSF samples;
genotype completion 99%) were extracted from the
postimputation ISHDSF data set. An identical filtering
procedure was performed for Affymetrix 6.0 and imputed
SNPs in the WTCCC sample. Of 1.25 M SNPs in the
PGC stage-I analysis, 540576 met our filtering criteria in
both cohorts. In constructing the initial polygene score,
we identified 289541 SNPs that yielded a P value of less
than .2 in the PGC stage-I results. Although the choice of
P value threshold is somewhat arbitrary, inclusion of a
relatively large number of SNPs is preferable. We decided
to use a threshold of P < .2 because it approximates a
P value of .159, which corresponds to the inclusion
threshold from Akaike information criterion.35 Of these,
137 957 SNPs were available in both cohorts following
postimputation filtering. Let Gij denote the additive
genotype for ith SNP in the jth subject; let pi and i

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

minor allele frequency (MAF) <1%; call rate <98%; and

GenCall10 quality score <0.55. Following lift-over to
the most recent genome assembly (GRCh37.2), 557373
autosomal SNPs were available for analysis; genotyping
completion was greater than99.9%.
In order to investigate the possibility of duplicated or
erroneously identified DNAs, we compared estimates of
genetic relatedness (identity-by-descent) generated using
PLINK27 against expectation based on known familial
relationships. The majority of observed inconsistencies
were instances of a single, duplicated sample labeled
falsely as representing an affected sib-pair. For sex-discordant sib-pairs, the true identity of a duplicate sample was
resolved by consideration of X-chromosome genotypes.
Following exclusion of problematic samples, a total of
843 individuals representing 237 pedigrees remained for
analysis.

Molecular Validation of the Schizophrenia Spectrum

Determination of Empirical Significance

In order to assess the empirical significance of the observed
polygene score distribution in the ISHDSF, we generated
1000 null replicates of the PGC stage-I results for SCZ.
We simulated N = 20000 diploid individuals from N = 379
European individuals in the April 2012 release of the 1000
Genomes Project data. Autosomal SNP data for simulated individuals was obtained by sampling 44 times (with
replacement) from 379 2 = 758 reference haplotypes.
Assignment of disease status was random:
10 000 affected and 10 000 unaffected individuals.
These phenotypic definitions were then shuffled 1000
times. Each null phenotype was analyzed using the logistic regression procedure in PLINK27, as to obtain a direct
estimates of the OR. From each set of null association
results, we extracted SNPs yielding P values in the first
quintile (P < .2), as describedabove.
For each null replicate, we used PLINK to obtain an
LD-pruned set of independent SNPs based on a panel
consisting of available WTCCC samples and N = 286
independent ISHDSF samples. These pruned SNP sets
served as the basis for calculating 1000 null polygene
scores. In calculating null polygene scores, we used the
associated allele frequencies reported in the PGC stage-I
results. Empirical significance was defined as the proportion of null replicates yielding a mean difference
in polygene score greater than the observed difference
between ISHDSF and population controls, (r + 1)/
(n + 1).36 If following 1000 permutations, no replicate
more significant than the actual finding was observed,
we report a conservative estimate of the empirical
P value, ie, P .002.

and unaffectedN = 217 individuals in 142 families. The

sample sizes in the broad and very broad categories were
too small to meaningfully examine on their own and so
were combined for subsequent analyses (N = 92 individuals in 71 families).
The mean schizophrenia polygene scores (and SEs) in
each of the 4 diagnostic classes of relatives from the highdensity pedigrees are displayed in figure1. The observed
pattern is consistent with that expected under the hypothesis of the schizophrenia spectrum with the narrow category having the highest score and the score decreasing in
a nearly monotonic function across the other diagnostic
categories. A one-way ANOVA, the single best test for
the hypothesized schizophrenia spectrum, but unadjusted
for relatedness of subjects within and across diagnostic
categories, indicated a significant difference among these
diagnostic classes (P = .03). The mean polygene score was
highest in the narrow category (Z = 1.59, 95% CI=[1.47,
1.72]), similar in the intermediate and broad/very broad
categories (Z = 1.47, [1.24, 1.69] and Z = 1.48, [1.23,
1.73], respectively) and lowest in the family members
without any psychiatric diagnosis (Z = 1.32, [1.17, 1.47]).
Pair-wise comparisons of diagnostic categories, adjusted
for pedigree structure using a random-effects model,
indicated significant differences (by a likelihood ratio test)
between the narrow category and the intermediate, broad/
very broad, and unaffected categories (one-sided P values
of .022, .042, 7.68 106, respectively); nonsignificant

Results
Polygene Score by Categorical Diagnosis in the
Schizophrenia Spectrum
The numbers of relatives with polygene schizophrenia
scores in each of our 5 diagnostic classes were narrowN
= 432 individuals in 231 families; intermediateN = 95
individuals in 75 families; broadN = 33 individuals in
31 families; very broadN = 59 individuals in 49 families;

Fig. 1. Mean individual polygene scores for population controls

and for each of the diagnostic categories of the schizophrenia
spectrum made up of individuals from the Irish Study of High
Density Schizophrenia Families. Error bars represent the SE of
the observed mean.

63

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

denote the frequency and OR of the associated allele

for the ith SNP. Using an independent subset of k SNPs
(r2 < .2), we constructed a per-individual score, Sj, as
S j = i k (Gij 2pi ) log e (i ) . We obtained normalized
scores by randomly selecting an individual from each
family and calculating the SD; this procedure repeated
1000 times to obtain a final estimate of the SD. For
each categorical diagnosis in ISHDSF, we randomly
selected an affected individual from each pedigree (where
applicable) to obtain an estimate of the mean normalized
polygene score; we repeated this procedure 1000 times to
obtain a final estimate of the mean.

T. B.Bigdeli etal

differences between the intermediate category and broad/

very broad (P = .431) or unaffected categories (P = .216);
and a nonsignificant difference between the broad/very
broad and unaffected categories (P = .141).
Relative Enrichment Compared With Population
Controls

Discussion
We sought in this article to validate, using new molecular
methods, the concept of a genetically influenced schizophrenia spectrum, the origins of which can be traced back
to beginnings of modern psychiatry in the late 19th and
early 20th century. Our results replicated earlier family and
adoption studies showing a continuum of genetic risk, as
assessed by a polygene risk score based on variants found
to be associated with schizophrenia in GWAS data from
the PGC schizophrenia consortium,34 in blindly diagnosed
members of Irish pedigrees selected for a high risk for
schizophrenia. Members of those pedigrees with disorders in the narrow schizophrenia spectrum had the highest
polygene risk scores, followed by relatives with diagnoses
considered to be in the intermediate, broad, and very broad
part of the spectrum. Both of these groups of relatives had
schizophrenia polygene scores higher than relatives in these
pedigrees judged to be free of any psychiatric illness.
This report can be viewed as a direct attempt to verify
our prior modeling of the schizophrenia spectrum in the
Roscommon Family Study.16 Of interest, in that report,
we could with some confidence, determine the low- and
high-risk ends of the schizophrenia spectrum but were
less certain about the proper ordering of disorders in the
middle. Our findings, based on molecular variants rather
than statistical patterns of occurrence and cooccurrence
in relatives, reached a similar conclusion.
In the relatives of these high-density families, the
observed pattern of enrichment of molecular indices of
the risk to schizophrenia is congruent with an underlying, continuous liability distribution and, we submit, represents preliminary, molecular validation of a common
genetic basis for the schizophrenia spectrum disorders.
64

Limitations
These results should be interpreted in the context of 3
potentially important methodological limitations. First,
the members of familial samples were selected for highthroughput genotyping based on the informativeness of
their genetic relationships for association analysis. That
is, schizophrenic probands and their unaffected firstdegree relatives were preferentially selected for inclusion in a primary GWAS of schizophrenia. We therefore
do not have samples on all members of these pedigrees
available for molecular analysis. Second, ascertainment
for the ISHDSF required at least 2 first-degree relatives
with a primary diagnosis of schizophrenia or simple
schizophrenia; eligibility did not require the incidence
of schizophrenia spectrum disorders in a given pedigree.
Therefore, the various diagnostic categories considered
herein are not equivalently represented across all pedigrees, with a substantial proportion of spectrum cases
originating from a subset of larger families and multiplex sibships. Third, the schizophrenia polygene scores
utilized in these analyses account for only a modest
proportion of total disease variance and surely do not
index all aspects of the genetic risk for schizophrenia.
For example, genetic risks that arise from rare variants
or large structural genomic changes (ie, copy number
variants) are not well represented in the polygene score.
We cannot be certain if their inclusion would result in a
different pattern of findings.
Funding
The United States National Institutes of Health (MH41953, MH-083094, and MH-068881).
Acknowledgment
The authors have declared that there are no conflicts of
interest in relation to the subject of this study.
References
1. Kraepelin E. Dementia Praecox and Paraphrenia. Huntington,
NY: Krieger Publishing; 1971.
2. Bleuler E. Dementia Praecox, or The Group of Schizophrenias.
New York, NY: International Universities Press; 1950.

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

The mean schizophrenia polygene scores for the 929 Irish

controls was estimated at Z = 0.96, (0.90, 1.02). As calculated from 1000 permutations, this score was significantly
lower than those observed in any of the 4 of the diagnostic classes of relatives from the ISHDSF (P < .002). We
estimated the variance explained by the polygene score as
6.33% for the narrow category, 1.87% and 1.85% for the
intermediate and broad/very broad categories, and 1.61%
for unaffected relatives. Anearly identical pattern of findings was observed for polygene scores based on P value
thresholds of .1 and .05 although the variance explained
by these scores was lower at progressively more stringent
thresholds.

We also compared the polygene scores calculated in

the diagnostic classes of the high-density schizophrenia
families with those obtained from a large group of ethnically matched controls. All diagnostic classes in the
high-density families were highly significantly enriched
for polygene schizophrenia risk. As would be expected
for any reasonable model of genetic transmission, individuals who are unaffected but close relatives of multiple
individuals with schizophrenia or schizophrenia spectrum disorders are at an elevated geneticrisk.

Molecular Validation of the Schizophrenia Spectrum

Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry. 2011;16:429441.
20. Riley B, Thiselton D, Maher BS, etal. Replication of association between schizophrenia and ZNF804A in the Irish CaseControl Study of Schizophrenia sample. Mol Psychiatry.
2010;15:2937.
21. Yasuda Y, Hashimoto R, Ohi K, et al. Impact on schizotypal personality trait of a genome-wide supported psychosis variant of the ZNF804A gene. Neurosci Lett.
2011;495:216220.
22. Stefanis NC, Hatzimanolis A, Avramopoulos D, et al.
Variation in psychosis gene ZNF804A is associated with a
refined schizotypy phenotype but not neurocognitive performance in a large young male population. Schizophr Bull.
2012.
23. Purcell SM, Wray NR, Stone JL, et al. Common polygenic
variation contributes to risk of schizophrenia and bipolar
disorder. Nature. 2009;460:748752.
24. Spitzer RL, Williams JB, Gibbon J. Structured Clinical
Interview for DSM-III-R - Patient Version (SCID-P, 4/1/87).
New York: New York State Psychiatric Institute; 1987.
25. Kendler KS, Lieberman JA, Walsh D. The Structured
Interview for Schizotypy (SIS): a preliminary report.
Schizophr Bull. 1989;15:559571.
26. Endicott J, Andreasen N, Spitzer RL. Family HistoryResearch Diagnostic Criteria. New York, NY: New York
State Psychiatric Institute, Biometrics Research Department;
1975.
27. Purcell S, Neale B, Todd-Brown K, etal. PLINK: a tool set
for whole-genome association and population-based linkage
analyses. Am J Hum Genet. 2007;81:559575.
28. Irish Schizophrenia Genomics Consortium, Wellcome Trust
Case Control Consortium 2. Genome-wide association
study implicates HLA-C*01:02 as a risk factor at the major
histocompatibility complex locus in schizophrenia. Biol
Psychiatry. 2012;72:620628.
29. Browning BL, Yu Z. Simultaneous genotype calling and
haplotype phasing improves genotype accuracy and reduces
false-positive associations for genome-wide association studies. Am J Hum Genet. 2009;85:847861.
30. Delaneau O, Marchini J, Zagury JF. A linear complexity
phasing method for thousands of genomes. Nat Methods.
2012;9:179181.
31. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet.
2009;5:e1000529.
32. Abecasis GR, Auton A, Brooks LD, etal. An integrated map
of genetic variation from 1,092 human genomes. Nature.
2012;491:5665.
33. Howie B, Marchini J, Stephens M. Genotype imputation with
thousands of genomes. G3 (Bethesda). 2011;1:457470.
34. Ripke S, Sanders AR, Kendler KS, etal. Genome-wide association study identifies five new schizophrenia loci. Nat Genet.
2011;43:969976.
35. Akaike H. A new look at the statistical model identification.
IEEE Trans Autom. Cont. 1974;19:716723.
36. North BV, Curtis D, Sham PC. A note on calculation of
empirical P values from Monte Carlo procedure. Am J Hum
Genet. 2003;72:498499.

65

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Virginia Commonwealth Universtiy on March 24, 2014

3. Kendler KS. Diagnostic approaches to schizotypal personality disorder: a historical perspective. Schizophr Bull.
1985;11:538553.
4. Zerbin-Rudin E, Kendler KS. Ernst Rudin (1874-1952) and
his genealogic-demographic department in Munich (19171986): an introduction to their family studies of schizophrenia. Am J Med Genet. 1996;67:332337.
5. Kallmann FJ. The Genetics of Schizophrenia. New York, NY:
J.S. Augustin; 1938.
6. Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen
B. Mental illness in the biological and adoptive families of
adopted individuals who have become schizophrenic: a preliminary report based on psychiatric interviews. In: Fieve R,
Rosenthal D, Brill H, eds. Genetic Research in Psychiatry.
Baltimore, MA: Johns Hopkins Press; 1975:147165.
7. Kety SS, Wender PH, Jacobsen B, etal. Mental illness in the
biological and adoptive relatives of schizophrenic adoptees.
Replication of the Copenhagen Study in the rest of Denmark.
Arch Gen Psychiatry. 1994;51:442455.
8. Kety SS. Schizophrenic illness in the families of schizophrenic adoptees: findings from the Danish national sample.
Schizophr Bull. 1988;14:217222.
9. Spitzer RL, Endicott J, Gibbon M. Crossing the border into
borderline personality and borderline schizophrenia. The
development of criteria. Arch Gen Psychiatry. 1979;36:1724.
10. Baron M, Gruen R, Asnis L, Kane J. Familial relatedness
of schizophrenia and schizotypal states. Am J Psychiatry.
1983;140:14371442.
11. Kendler KS, McGuire M, Gruenberg AM, OHare A,
Spellman M, Walsh D. The Roscommon Family Study.
I.Methods, diagnosis of probands, and risk of schizophrenia
in relatives. Arch Gen Psychiatry. 1993;50:527540.
12. Kendler KS, McGuire M, Gruenberg AM, Spellman M,
OHare A, Walsh D. The Roscommon Family Study. II. The
risk of nonschizophrenic nonaffective psychoses in relatives.
Arch Gen Psychiatry. 1993;50:645652.
13. Kendler KS, McGuire M, Gruenberg AM, OHare A,
Spellman M, Walsh D. The Roscommon Family Study. III.
Schizophrenia-related personality disorders in relatives. Arch
Gen Psychiatry. 1993;50:781788.
14. Kendler KS, Gruenberg AM, Kinney DK. Independent diagnoses of adoptees and relatives as defined by DSM-III in the
provincial and national samples of the Danish Adoption Study
of Schizophrenia. Arch Gen Psychiatry. 1994;51:456468.
15. Asarnow RF, Nuechterlein KH, Fogelson D, et al.
Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: the UCLA family study. Arch Gen Psychiatry.
2001;58:581588.
16. Kendler KS, Neale MC, Walsh D. Evaluating the spectrum
concept of schizophrenia in the Roscommon Family Study.
Am J Psychiatry. 1995;152:749754.
17. Kendler KS, ONeill FA, Burke J, etal. Irish study on highdensity schizophrenia families: field methods and power to
detect linkage. Am J Med Genet. 1996;67:179190.
18. Fanous AH, Neale MC, Gardner CO, etal. Significant correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy. Mol Psychiatry. 2007;12:958965.
19. Williams HJ, Norton N, Dwyer S, etal.; Molecular Genetics
of Schizophrenia Collaboration (MGS) International
Schizophrenia Consortium (ISC), SGENE-plus, GROUP.