SCHRES-05880; No of Pages 11

Schizophrenia Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres

Review

Genetic underpinnings of white matter ‘connectivity’: Heritability, risk,

and heterogeneity in schizophrenia
Aristotle N. Voineskos ⁎
Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Canada
Institute of Medical Science, University of Toronto, Canada
Department of Psychiatry, University of Toronto, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Schizophrenia is a highly heritable disorder. Thus, the combination of genetics and brain imaging may be a useful
Received 23 January 2014 strategy to investigate the effects of risk genes on anatomical connectivity, and for gene discovery, i.e. discovering
Received in revised form 11 March 2014 the genetic correlates of white matter phenotypes. Following a database search, I review evidence for heritability
Accepted 12 March 2014
of white matter phenotypes. I also review candidate gene investigations, examining association of putative risk
Available online xxxx
variants with white matter phenotypes, as well as the recent flurry of research exploring relationships of
Keywords:
genome-wide significant risk loci with white matter phenotypes. Finally, I review multivariate and polygene
White matter approaches, which constitute a new wave of imaging-genetics research, including large collaborative initiatives
Genetics aiming to discover new genes that may predict aspects of white matter microstructure. The literature supports
Diffusion tensor imaging the heritability of white matter phenotypes. Loci in genes intimately implicated in oligodendrocyte and myelin
Heritability development, growth and maintenance, and neurotrophic systems are associated with white matter microstruc-
Quantitative trait ture. GWAS variants have not yet sufficiently been explored using DTI-based evaluation of white matter to draw
GWAS conclusions, although micro-RNA 137 is promising due to its potential regulation of other GWAS schizophrenia
Schizophrenia
genes. Many imaging-genetic studies only include healthy participants, which, while helping control for certain
confounds, cannot address questions related to disease heterogeneity or symptom expression, and thus more
studies should include participants with schizophrenia. With sufficiently large sample sizes, the future of this
field lies in polygene strategies aimed at risk prediction and heterogeneity dissection of schizophrenia that can
translate to personalized interventions.
© 2014 Elsevier B.V. All rights reserved.

1. Introduction
In the past 5 years, needles in the complex haystack of schizophrenia
genetics have been uncovered (O'Donovan et al., 2008; Stefansson et al.,
2008; Stefansson et al., 2009; 2011; Ripke et al., 2013). Sample sizes in
the tens of thousands have now convincingly established schizophrenia
risk loci, just as such large samples were required in other disorders
(Ripke et al., 2013). Now, as genetic risk loci emerge, the challenge is
to identify where, when, and how these loci confer risk for schizophre-
nia. Furthermore, some of these risk loci may provide important clues
regarding dissecting the heterogeneity of schizophrenia. The ‘bottom-
up’ opportunity of imaging-genetics today is to help characterize the
effects of these risk loci on vulnerable brain circuitry both in healthy
people and in people with schizophrenia. The ‘top-down’ opportunity
of imaging-genetics is to use large sample sizes with both neuroimaging
and genetic information to identify novel loci or confirm existing
genetic risk loci from schizophrenia GWAS based on neuroimaging
⁎ 7th Floor, 250 College St, Toronto, Ontario M5T 1R8, Canada. Tel.: +1 416 535
8501x4378; fax: +1 416 979 6936.
E-mail address: Aristotle.Voineskos@camh.ca.
phenotypes using a quantitative trait locus (QTL) based approach. The
field is now in a position to understand the effects of genetic loci that
contribute to variation in white matter neuroimaging phenotypes,
and in the process map the genetic underpinnings of white matter
dysconnectivity that is a critical neurobiological feature for many people
suffering from schizophrenia (Shenton et al., 2010).
The purpose of this manuscript is to review what is known regarding
the underlying genetic architecture of white matter phenotypes (with a
focus on diffusion tensor imaging phenotypes), based on work done in
healthy subjects and from schizophrenia patients. While there is little
doubt that there is shared genetic vulnerability that cuts across psychi-
atric disorders, a review of the shared and unique genetic factors under-
lying potential white matter disruption in mental illnesses such as
bipolar disorder, autism spectrum disorder, or major depressive disor-
der is beyond the scope of this manuscript.
To find English language references relevant to the present review on
imaging-genetics in white matter in schizophrenia, a sensitive search
strategy was conducted in three relevant article databases (MEDLINE
(1946–2014), EMBASE (1974–2014) and PsychINFO (1967–2014))
using the OvidSP platform. Search terms included “heritability”, “white
matter”, “magnetic resonance imaging”, “diffusion tensor imaging”,

http://dx.doi.org/10.1016/j.schres.2014.03.034
0920-9964/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
2 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx
“genetics”, “genome-wide association”, “schizophrenia”, and
“psychosis”. All titles and abstracts were screened, and full-text versions
of articles deemed relevant to the present review were then obtained.
Results of the review are described primarily in Sections 2–5, with
Table 1 specifically highlighting the results of association studies of
genome-wide significant variants for schizophrenia with white matter
phenotypes.
2. Heritability of white matter phenotypes
Strong heritability is a principal tenet in genetic studies relying on
the utility of a phenotype other than the disease phenotype. With re-
spect to white matter, the neuroimaging phenotype could be either
volumetric, based on diffusion-weighted parameters, magnetization
transfer ratio imaging, related to white matter hyperintensity, or quan-
titative T1 or T2-weighted imaging. Among these neuroimaging mea-
sures, volumetric and diffusion-based parameters have been most
studied in schizophrenia. The region (or tract) of interest, the choice
of voxel-wise vs. region-of-interest (ROI) or tract-based analysis, and
the timepoint in the lifespan of the human sample studied can all affect
the heritability estimate, among other factors. Heritability studies are
typically conducted using both monozygotic and dizygotic twins, al-
though studies using parents and siblings can also be conducted.
2.1. Heritability studies of white matter volume
One of the first heritability studies to examine white matter volume
examined 54 monozygotic (MZ) and 58 dizygotic (DZ) twins and 34 of
their full siblings using MRI. The authors estimated that genetic factors
accounted for 88% of the individual differences in white matter volume.
The authors also found that genes influencing gray and white matter
overlapped to a large extent and completely determined their pheno-
typic correlation (Baare et al., 2001). Another early study focused on
the corpus callosum and showed that high heritability estimates (e.g.
79% for the midline cross-sectional area) were present through
late adult life (i.e. into the seventh and eighth decades of life)
(Pfefferbaum et al., 2000), supported by another study which found
even higher heritability (Scamvougeras et al., 2003). One study that ex-
amined MZ twins found very high correlation coefficients (r N 0.90) for
white matter volumes in MZ twin pairs, a value much higher than that
present in matched controls (White et al., 2002). In children, additive
genetic effects accounted for a substantial proportion of the variability
in white matter volume (Wallace et al., 2006). When the above initial,
small studies are taken together, one could conclude that white matter
volumes are highly heritable across the lifespan.
Another approach is to study MZ twins discordant for disease to as-
sess genetic and environmental risk factors. A small study of 11 MZ and
11 same-gender DZ twin pairs discordant for schizophrenia found de-
creased white matter volume in discordant twin pairs compared with
healthy twin pairs, particularly in the MZ twin pairs. A decrease in
gray matter was found in the patients compared with their co-twins
and compared with the healthy twins. The authors concluded that the
decrease in white matter volume reflected the increased genetic risk
to develop schizophrenia, whereas the decreases in grey matter volume
were related to environmental risk factors, highlighting the importance
of genetic contributions to white matter structures in schizophrenia
(Hulshoff Pol et al., 2004). The same group, appearing to use the same
twin pairs at longitudinal 5-year follow-up reported interesting data ex-
ploring percentage volume change over time. The authors found signif-
icant additive genetic influences on the correlations between
schizophrenia liability and progressive brain volume changes; however,
progressive change in white matter did not appear to have genetic influ-
ence over and above that of gray matter (Brans et al., 2008).
This manuscript does not review all structural MRI studies that have
assessed the heritability of white matter volumes. However, recent
studies publishing on large samples can help provide more conclusive
Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
insight into the heritability of white matter volumes. A recent meta-
analysis identified over 50 such studies (many of which also assessed
gray matter volumes, cortical thickness, and other neuroimaging phe-
notypes derived from T1-weighted imaging). The results of this meta-
analysis (Blokland et al., 2012) supported strong genetic effects on
total and regional white matter volumes. Across the lifespan, studies
continue to support heritability of white matter volume in large sam-
ples. A study of 8 year old twins, 57 MZ and 35 DZ (Quebec Newborn
Twins Study, or QNTS) showed additive genetic effects of left and
right brain white matter volume (81%) (Yoon et al., 2010). In neonatal
twins, heritability of total white matter volume is also very high (85%)
(Gilmore et al., 2010). While genetic effects on brain structure may
not be as prominent in later-life (Batouli et al., 2013), heritability of
white matter volumes toward the end of the human lifespan remain
high, and in fact are higher than gray matter or CSF, as shown in the
older Australian twins study (OATS) which consisted of 154 MZ and
82 DZ individuals, aged 65 or older (Batouli et al., 2014). Therefore, it
appears that white matter volume is a stable and highly heritable phe-
notype across the lifespan. However, assessment of white matter tissue
is limited using volumetric approaches, from the perspective of both
measurement and visualization. Diffusion-weighted imaging ap-
proaches can overcome some of these limitations (Jones, 2008).
2.2. Heritability studies of Diffusion Tensor Imaging (DTI) derived measures
Over the past ten years, the field has gravitated toward the use of
Diffusion Tensor Imaging, or DTI (Basser et al., 1994) in imaging-
genetics studies of white matter. DTI via measurements of diffusion an-
isotropy and diffusivity provides an index of tissue microstructure, can
localize effects to specific white matter tracts, and can provide informa-
tion on tract integrity and potentially on axonal and myelin architec-
ture. The first DTI heritability study was small: 15 MZ and 18 DZ twin
pairs of elderly men were studied from the National Heart, Lung, and
Blood Institute Twin study (NHLBI), and FA in the genu and splenium
of the corpus callosum were the neuroimaging measures of interest
(Pfefferbaum et al., 2001). The authors found that genetic contributions
explained 67% and 49% of the total variance in FA respectively in the
genu and splenium. However, a study of 23 MZ and 23 DZ twin pairs
from the Queensland Twin Imaging Study (QTIMS) showed that genetic
factors explained 75–90% of the variance in FA in almost all white mat-
ter regions (Chiang et al., 2009b). Closer to the beginning of the lifespan,
the same group examined 705 twins (129 MZ and 170 DZ) and their sib-
lings aged 12 to 29 from QTIMS, and heritability of FA across white mat-
ter tracts using a voxel-wise approach was calculated (Chiang et al.,
2011b). The authors also considered effects of age, sex, IQ, and socioeco-
nomic status. They found that in those individuals with above average
IQ, heritability was greater than 80% in thalamus, genu, posterior inter-
nal capsule and corona radiata, while in those with below average IQ, FA
heritability dipped down to approximately 40%. They also found that in
adolescents, 70–80% of the variation in FA was due to genetic factors,
while in adults only 30–40% of the variation in FA was similarly attribut-
able. Finally, male sex was also associated with higher heritability.
While this study had a very impressive sample size, the authors used
smoothing in their postprocessing routine and acquired anisotropic
voxels, both of which can confound results (Jones et al., 2002; Jones
et al., 2005). Another study from the same sample assessed n = 374
healthy adults (60 MZ pairs, 45 DZ pairs and 164 mixed sex DZ twins
and siblings) to understand genetic effects on white mater asymmetry.
Modest genetic effects (10–37% depending on the structure) were
found. Sex differences in asymmetry were also present (Jahanshad
et al., 2010).
An even younger sample of MZ and DZ twins consisting of 9 year old
children (total n = 185) from the Netherlands Twin Registry (NTR) and
Utrecht Medical Centre Twin Sample (UMCTS), used DTI with fiber
tractography to assess heritability of FA, radial diffusivity (RD), axial or
longitudinal/axial diffusivity (AD), and of magnetization transfer ratio
 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx 3

Table 1
Details of studies examining association of genome-wide significant loci for schizophrenia with white matter phenotypes.

Gene White matter phenotype Sample Finding Reference

ZNF804A T1-weighted MRI N = 39 healthy controls (Caucasian) Association with total white matter Lencz et al. (2010)
Total white matter volume and
lobar white matter volume
ZNF804A DTI tractography–Fronto-temporal N = 62 healthy controls (Caucasian) No association Voineskos et al.
and interhemispheric white matter FA (2011b)
ZNF804A DTI–tract based spatial statistics (TBSS)–FA N = 53 healthy controls No association Sprooten et al.
throughout white matter skeleton; ROI and N = 84 healthy controls (2012)
tractography N = 50 unaffected relatives of bipolar
subjects (Caucasian)
ZNF804A T1-weighted MRI N = 69 healthy controls Genotype by diagnosis interaction Wei et al. (2012)
White matter density N = 80 people with schizophrenia (Risk allele with higher WM density in scz,
(Han Chinese) and lower in healthy in left prefrontal lobe)
ZNF804A DTI–mean FA analysis of lobar N = 75 controls Genotype by diagnosis interaction Kuswanto et al.
white matter N = 125 people with schizophrenia (FA of parietal, temporal, cingulate WM) (2012)
regions (Chinese)
ZNF804A T1-weighted MRI N = 198 controls Risk allele carriers in both group had Wassink et al.
Lobar white matter volumes N = 335 people with a schizophrenia larger WM volumes (2012)
spectrum
disorder (Caucasian)
ZNF804A DTI–TBSS–FA, MD, AD, RD throughout N = 69 controls No association Wei et al. (2013)
white matter skeleton N = 100 people with schizophrenia
(Han Chinese)
CACNA1C DTI–TBSS–predefined hippocampal ROI FA N = 100 controls (Caucasian) Risk allele associated with reduced right Dietsche et al.
hippocampal FA (2014)
Neurogranin T1-weighted MRI N = 263 controls No association Ohi et al. (2012)
VBM N = 99 people with schizophrenia
(Japanese)
Neurogranin T1-weighted MRI N = 140 controls No association Rose et al. (2012)
VBM (Caucasian)
ANK3 DTI–volume of interest in anterior limb of N = 88 controls (Caucasian) Lower FA and AD of anterior limb of internal Linke et al. (2012)
internal capsule followed by tractography capsule in those with risk genotype
MHC T1-weighted MRI N = 173 controls No association Agartz et al. (2011)
Lobar white matter volumes N = 247 schizophrenia spectrum and
bipolar spectrum disorder (Caucasian)
MHC T1-weighted MRI N = 892 controls (Caucasian) No association Walters et al.
ZNF804A Voxel-based morphometry (VBM) (2013)
Cousijn et al. (2012)
CSMD1 T1-weighted MRI N = 150 controls No association Rose et al. (2013)
VBM (Caucasian)
CNNM2 T1-weighted MR N = 159 controls No association Rose et al. (2014)
VBM N = 39 controls
(Caucasian)
MIR137 DTI–TBSS–Whole Brain white N = 121 controls Risk allele homozygotes with schizophrenia had Lett et al. (2013)
matter skeleton mean FA N = 92 people with schizophrenia lower white matter FA compared to protective
(Caucasian) allele carriers
VRK2 T1-weighted MRI N = 286 Association of risk allele with total Li et al. (2012)
VBM Han Chinese white matter volume
RELN DTI–TBSS followed by FA N = 93 No association Tost et al. (2010)
measurement of specific ROIs Caucasian

(MTR) (Brouwer et al., 2010). The authors studied the genu and
splenium of the corpus callosum, and left and right uncinate and supe-
rior longitudinal fasciculi. Significant genetic influences could not be
established for FA. However, genetic factors significantly explained var-
iation in both longitudinal/axial and radial diffusivity (especially the lat-
ter), as well as MTR. Both MTR and radial diffusivity heritability values
were highest at the superior longitudinal fasciculus. However, a study
of neonatal twin pairs (Geng et al., 2012) found significant heritability
across all three average diffusion parameters studied over whole brain
white matter. FA had the highest heritability (.60) followed by axial
(longitudinal) diffusivity (.57), and radial diffusivity (.53). There was
considerable variation across white matter regions or tracts, which
might help explain the lack of findings from the previous study of
9 year olds, where only a small number of tracts were examined. In
the neonatal study, among white matter tracts, FA heritability was
highest at left posterior corona radiata (.82), with highest RD heritabil-
ity (all N 0.80) in left middle and inferior occipital gyrus, right pre-
cuneus, right inferior temporal gyrus, deep white matter regions of
right sagittal stratum, right splenium of corpus callosum, and left poste-
rior corona radiata. For AD, right posterior corona radiata showed
heritability of 0.92. Other tracts with high heritability included the unci-
nate fasciculus (0.62), genu, body, and splenium of corpus callosum
(.72, .69, .68), and cingulate gyrus (.68). Overall FA heritability, unlike
RD heritability, did not increase in regions with higher FA. Extending
out toward the end of the lifespan, a family study (San Antonio Family
Heart Study or SAFHS) of 467 healthy individuals, ranging in age from
19 to 85, found significant genetic contributions to FA and radial diffu-
sivity (but not longitudinal diffusivity) following TBSS and tract-based
calculations of diffusion parameters with the help of the JHU atlas
(Kochunov et al., 2010). The authors used 417 markers spaced at ap-
proximately 10-centiMorgan intervals across 22 autosomes. Whole
brain FA showed the highest heritability (.52) among all diffusion pa-
rameters followed by radial diffusivity (.37). The genetic factors that
produced increases in radial diffusivity were also responsible for de-
creases in FA. However, there were no significant age by sex or age-
squared by sex covariates.
Others have looked at a combination of white matter FA and cogni-
tive performance in heritability studies. In one of the same studies brief-
ly described above (Chiang et al., 2009b), in 92 identical and fraternal
twins (23 pairs of each), the anatomical profile of correlations between

Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
4 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx
white matter FA and full-scale, verbal, and performance intelligence
quotients was examined. In addition to showing relatively strong corre-
lations of white matter FA with intellectual performance, the authors
implicated the same genes as mediating the correlation between IQ
and white matter integrity, using an approach that whereby the IQ of
one twin was predicted with high precision from the white matter in-
tegrity of the other twin. In a study using unaffected relatives, examin-
ing 22 participants at genetic risk for schizophrenia, 23 people with
schizophrenia, and 37 non-psychiatric controls, both reductions and in-
creases in FA were found in different regions in the high-risk partici-
pants in relation to the comparison participants (Hoptman et al.,
2008). In a larger study, including the same participants both white
matter FA and cognitive performance were found to be heritable
(Bertisch et al., 2010).
Meta-analytic studies and multi-site analyses support the heritability
of white matter FA. A recently published meta-analysis (Blokland et al.,
2012), based on two studies and a small number of twin pairs found
tight confidence intervals for FA based measures with moderate heritabil-
ity values for superior longitudinal fasciculus, and genu and splenium of
the corpus callosum. A much larger ‘mega-analysis’, a specific data
pooling strategy, of 5 samples (4 twin samples and 1 family sample)
from the ENIGMA working group, using a total sample size of 2,248 indi-
viduals found robust and consistent heritability values for FA of all white
matter tracts examined except for the cortico-spinal tract, with heritabil-
ity values mainly ranging from 0.4 to 0.7. The investigators combined
much of the data from some of the samples described in the present re-
view along with others. One important finding was that datasets with
smaller numbers of subjects were more likely to produce heritability esti-
mates not representative of the pooled trend. Overall, pooled heritability
estimates across the brain were shown to be regionally uniform with ad-
ditive genetic factors explaining over 50% of inter-subject variance in FA
values (Kochunov et al., in press). The ROI template used in this study
was shown to be reliable for integrating multiple datasets, and supported
preliminary heritability results in a subset of n = 400 individuals from the
same twin and pedigree samples (Jahanshad et al., 2013). A multi-site col-
laborative neuroimaging and genetic effort known as the B-SNIP (Bipolar
Schizophrenia Network on Intermediate Phenotypes) consortium recent-
ly studied 513 participants with schizophrenia, psychotic bipolar disorder,
their first degree relatives, and healthy controls. The authors found that
both disease groups showed lower FA than comparison subjects in multi-
ple regions, with more marked differences in schizophrenia. Furthermore,
similar, but smaller effects were seen in schizophrenia relatives, with a
continuous FA decrease from healthy subjects to relatives to probands.
Overall, the authors found that white matter FA was highly heritable in
their sample, supporting its value as a potential endophenotype
(Skudlarski et al., 2013). When combining samples into larger mega- or
meta-analyses, the use of tractography data generated from different pro-
cessing methods (e.g. probabilistic vs. deterministic) might confound
results. One approach to circumvent this issue has been described by
the ENIGMA working group through the use of mega-analysis via utiliza-
tion of a common ROI-based template. The tradeoff, however, is that more
sophisticated methods of white matter analysis are not presently used in
large mega or meta-analytic imaging-genetic studies.
The unifying result of heritability studies with large sample sizes is
that white matter phenotypes are heritable. Both white matter volume
and white matter FA are heritable. It appears that heritability may vary
depending on the white matter tract under study; however, moderate
or high heritability appears to be the norm for nearly all white matter
tracts, with the exception possibly, of the corticospinal tract. Such herita-
bility appears to be relatively consistent throughout the lifespan, although
it might be slightly higher during the neonatal period and childhood.
3. White matter phenotypes as quantitative trait loci
There are surprisingly few studies addressing the underlying genetic
architecture of white matter structure using a quantitative trait locus
Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
(QTL) genomic strategy. This stands in contrast to several studies
using volume of subcortical structures as a quantitative trait, initially
using the ADNI dataset (e.g. hippocampal volume (Potkin et al., 2009),
caudate volume (Stein et al., 2011), and now through the ENIGMA
working group (e.g. for hippocampal volume (Bis et al., 2012; Stein
et al., 2012). The study by Stein et al. in n = 21,151 healthy individuals
revealed significant association of an intergenic variant, rs7294919 with
hippocampal volume. The first study using a DTI-based phenotype as a
QTL analysis in 467 healthy individuals recruited from randomly-
ascertained pedigrees of extended families found possible linkage at re-
gions 15q25 and 3q27 (LOD scores of 2.36 and 2.24 respectively). The
first region contains the major depressive disorder 2 gene as well as
the semaphorinprecursor 4B gene (which is involved in axonal exten-
sion and growth). The second region includes the adiponectin gene
and serotonin receptor-like 3D and 3E genes (Kochunov et al., 2010).
More recently global FA (derived from a principal components analysis
of 12 white matter tracts) was used as a quantitative phenotype in a
GWAS in elderly individuals from the Lothian Birth Cohort (n = 668).
No single SNP achieved GWAS significance; although there was sugges-
tive evidence (p values of 10− 6) at the ADAMTS18 gene, related to
tumor suppression and homeostasis and the LOC388630 gene, which
is of unknown function (Lopez et al., 2012). The ENIGMA-DTI working
group is now positioned, however, to conduct a genome-wide analysis
of white matter FA in many thousands of individuals, and other working
groups have also combined DTI and genetic data numbering into the
thousands (Blokland et al., 2013). Therefore, with this considerable in-
crease in statistical power, new genes associated with white matter FA
at genome-wide significant levels will almost certainly be discovered.
4. Candidate genes and gene systems: A Focus on Oligodendrocytes,
Axons, and Myelin, Neurodevelopmental and Neurotrophic Path-
ways and Relationship with White matter phenotypes
Genes involved in oligodendrocyte, myelin, and axonal development
and maintenance were logical early choices in candidate gene studies of
white matter phenotypes. In particular, genes of the neuregulin1-
tyrosine kinase receptor ErbB4 (NRG1-ErbB4) gene system and oligo-
dendrocyte/myelin (OM) system genes were of high interest, and
expression of these systems is coordinated (Georgieva et al., 2006).
OM genes are predominantly expressed in oligodendrocytes and direct-
ly involved in their myelination (initiation, deposition, compaction, and
maintenance) (Davis et al., 2003) and trophic support (Segal et al.,
2007), axonal support (McTigue and Tripathi, 2008), and axo-glial inter-
actions (Pernet et al., 2008). NRG1 plays an important role in cortico-
cortical myelination during neurodevelopment (Chen et al., 2006),
and disruption of the NRG1-ErbB4 pathway in oligodendrocytes in ani-
mal models leads to alteration of the myelin sheath of major white mat-
ter tracts, reduced conduction velocity, and cognitive changes (Roy
et al., 2007). Effects of NRG1 variants on white matter integrity have
been shown in healthy controls in the anterior limb of the internal cap-
sule and subcortical medial frontal white matter respectively (McIntosh
et al., 2008; Winterer et al., 2008), and in schizophrenia patients in the
anterior cingulum (Wang et al., 2009). ErbB4 demonstrates coordinated
expression with OM genes, oligodendrocyte transcription factor-2
(OLIG2) and 2′,3, cyclic nucleotide 3′-phosphodiesterase (CNP), in post-
mortem brain (Georgieva et al., 2006), and a SNP in this gene was asso-
ciated with integrity of the uncinate fasciculus (Konrad et al., 2009), as
well as with the anterior limb of the internal capsule (Zuliani et al.,
2011) in healthy individuals. OM genes, i.e. CNP, OLIG2, myelin associat-
ed glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG),
and transferrin (TF), an iron gene, came to attention following the first
postmortem transcriptomic studies (Hakak et al., 2001) in schizophre-
nia. OM genes code for proteins that influence the microstructural com-
ponents of white matter tracts that form the main barriers to water
diffusion indexed using DTI. Iron genes also play an important role in
myelination, and most of the brain's iron is found in oligodendrocytes,
 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx
which maintain iron homeostasis in the brain. A recent study examined
genotypic variation in NRG1, MOG, and CNP with brain structure using
volumetric approaches, and showed that an NRG1 SNP and a MOG
SNP were associated with white matter volume (in schizophrenia pa-
tients and healthy controls respectively) (Cannon et al., 2012). Gene
variants in TF and HFE were examined in association with white matter
FA in 574 individuals (twins and siblings) and revealed a significant as-
sociation of the HFE rs1799945 SNP with FA in the external capsule, and
this allele was associated with decreased levels of serum transferrin
(Jahanshad et al., 2012). FA in cingulum and in the superior longitudinal
fasciculus was also associated with serum transferrin.
In animal models, the neurodevelopmental disrupted-in-
schizophrenia 1 (DISC1) gene interacts with the OLIG2 gene, as does
NRG1 to influence oligodendrocyte development (Wood et al., 2009).
In humans, the DSCI1Ser704Cys polymorphism has been associated
with decreased FA in prefrontal white matter of 22 Cys allele carriers
vs. 86 Ser/Ser individuals (Hashimoto et al., 2006), 10 Cys/Cys individ-
uals showed decreased white matter FA throughout much of the brain
vs. 38 Cys/Ser and 39 Ser/Ser healthy individuals (Sprooten et al.,
2011). In a study of n = 278 healthy individuals decreased network ef-
ficiency was found in Cys allele carriers compared to Ser homozygotes
(Li et al., 2013), measured using graph theoretical approaches applied
to FA of fiber tracts throughout the brain. Neurotrophic genes have
also been investigated in relation to white matter phenotypes, particu-
larly the brain derived neurotrophic factor (BDNF), which interacts
with the p75 neurotrophin receptor (Cosgaya et al., 2002), which itself
is an intimate binding partner of MAG, MOG, and Nogo to influence
myelination (Wang et al., 2002). Although there are negative findings
in healthy individuals (Montag et al., 2010), many more studies have
shown association of the val66met with white matter microstructure
(Kennedy et al., 2009; Chiang et al., 2011a). In the Chiang et al. study,
in 455 healthy subjects, composed of twins and families, the val-
variant significantly modulated the association between FA and a mea-
sure of intelligence in the splenium of the corpus callosum. The
val66met variant has also been shown using data from 258 healthy
adult twins and their non twin siblings to explain nearly all the total var-
iance in FA in the posterior cingulate gyrus (Chiang et al., 2009a). In the
Kennedy et al. study, no genotype-related differences were observed in
the genu of the corpus callosum, while the splenium demonstrated
genotype-dependent age-effects. Another study showed genotype-by-
age interactions for FA of white matter tracts connecting to the medial
temporal lobe (Voineskos et al., 2011a). The NTRK1 gene (also known
as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin in-
volved in nervous system development and myelination which has
been associated with risk for schizophrenia. A SNP at NTRK1, rs6336
was recently associated with FA in a study of 391 young healthy adults
(Braskie et al., 2012). The same group also found evidence for associa-
tion of NTRK3 variants (the NTRK3 gene is also known as TRKC)
which is implicated in oligodendrocyte and myelin development, with
white matter FA in a widespread manner (corpus callosum, inferior lon-
gitudinal fasciculus) (Braskie et al., 2013). When taken together these
results suggest that variation in OM genes, the NRG1-ErbB4 system,
and neurotrophin genes is associated with white matter microstruc-
ture. However, given the main effects shown by these gene variants,
it is not entirely clear whether these associations are relevant to
schizophrenia, and may not be disease specific. Furthermore, only
a subset of studies included schizophrenia patients, although those
that did suggest a main effect of these variants on microstructural
integrity of white matter, rather than one more prominent in either
patients or controls.
5. GWAS variants and relationship with white matter phenotypes
Since the first schizophrenia GWAS published in 2008 (O'Donovan
et al., 2008), collaborative initiatives have provided increasing sample
sizes and accompanying power, such that the latest results of the
Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
5
psychiatric genetics consortium (PGC) have identified 22 risk loci for
schizophrenia (Ripke et al., 2013). Risk loci identified at GWAS-
significant levels (typically a p value of 5 × 10−8) carry a degree of con-
fidence in the genetic association result that was not present prior to the
advent of GWAS. The first such variant, rs1344706, situated within the
zinc finger transcription factor 804A, or ZNF804A gene, was identified
as a risk locus with a myelin/oligodendrocyte transcription factor bind-
ing site (Riley et al., 2010). The first imaging-genetics study of this
GWAS variant showed association in healthy individuals with fronto-
temporal and prefrontal interhemispheric connectivity phenotypes
using functional neuroimaging (Esslinger et al., 2009); thus it might
have been expected that the same variant would be associated with
the corresponding fronto-temporal and interhemispheric white matter
connections; however, in an investigation using tract-based FA pheno-
types, no such association was found, although there was a relationship
with cortical thickness in fronto-temporal regions (Voineskos et al.,
2011b). Just prior to that result, others found an association of this var-
iant with volumetric measures of gray and white matter (Lencz et al.,
2010). Further, another group did not find association of the ZNF804A
SNP and white matter FA, using TBSS (Sprooten et al., 2012) in healthy
individuals. Studies of this ZNF804A variant in relation to white matter
phenotypes in patients with schizophrenia have not shown consistent
results. One study found a genotype-by-diagnosis interaction on white
matter density in the left prefrontal lobe (Wei et al., 2012), whereas an-
other by the same group found no association with ‘white matter integ-
rity’, on FA, MD, AD, or RD in either schizophrenia patients or healthy
controls (Wei et al., 2013) using TBSS. However, a large study found a
significant main effect association of this SNP, as well as an association
in patients with schizophrenia, on total white matter, and particularly
frontal white matter volume (Wassink et al., 2012), with another
study (Kuswanto et al., 2012) demonstrating a genotype-by-diagnosis
interaction in FA of white matter in parietal, temporal, and cingulate re-
gions. Yet an even larger study of n = 892 individuals found no associ-
ation of this SNP with white matter volume (Cousijn et al., 2012).
The L-type voltage-dependent calcium channel CAv1.2 (alpha-1C
subunit) (CACNA1C) gene was initially discovered in bipolar GWAS
and then subsequently was also found to be associated with schizophre-
nia at a genome-wide significant level (Green et al., 2010). Although
most of the imaging-genetics studies of this gene have used fMRI para-
digms (Bigos et al., 2010), a recent DTI study showed that the CACNA1C
SNP (rs1006737) was associated with FA in the right hippocampal for-
mation using a hypothesis-driven approach (Dietsche et al., 2014).
The neurogranin gene is another schizophrenia risk gene discovered
by GWAS (Stefansson et al., 2009). The neurogranin protein is a post-
synaptic protein that is expressed in the human brain and involved in
the regulation of calmodulin availability in neurons (Huang et al.,
2004). A small number of MRI studies have been completed in relation
to this gene, although none have used DTI. Two studies examined the ef-
fect of this neurogranin SNP (rs12807809) on white matter volume, but
no association was found (Ohi et al., 2012; Rose et al., 2012). The anky-
rin 3 (ANK3) gene has genome-wide supported evidence for association
with both schizophrenia and bipolar disorder (2011). ANK3 is a mem-
ber of the ankyrin family of proteins that link integral membrane pro-
teins to the underlying spectrin-actin cytoskeleton and is expressed in
CNS. ANK3 also directs the localization of potassium channel proteins
to the nodes of Ranvier (Judy et al., 2013). Healthy carriers of the
ANK3 rs10994336 risk genotype were shown to have lower FA and lon-
gitudinal diffusivity in the anterior limb of the internal capsule (Linke
et al., 2012).
Perhaps surprisingly, while the major histocompatability complex
(MHC) region provides the strongest statistical association with schizo-
phrenia in GWAS studies (Stefansson et al., 2009; Ripke et al., 2013),
few neuroimaging studies have been completed examining association
with GWAS SNPs (e.g. rs6904071) within MHC and brain structure.
None have been published with a focus on white matter imaging pheno-
types, although two large volumetric studies (Agartz et al., 2011;
6 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx
Walters et al., 2013) did explore brain volumes and no association with
white matter volume was reported. Another GWAS SNP, part of the
transcription factor 4 (TCF4) gene, was investigated in relation
to neuroimaging phenotypes, but not white matter phenotypes
(Wirgenes et al., 2012). TCF4 may play an important role in regulation
of oligodendrocyte differentiation and myelination (Emery, 2010) and
thus variation in this gene may influence white matter phenotypes in
schizophrenia either through TCF4 or through interaction with other
genes. The rs10503253 SNP within the CUB and Sushi multiple
domains-1 (CSMD1) gene, a tumor suppressor gene has also been iden-
tified as genome-wide significant for schizophrenia (2011). A voxel
based morphometry investigation of white matter volume showed no
association (Rose et al., 2013). This gene is thought to be involved in
complement control (Havik et al., 2011). The same group recently pub-
lished on the cyclin M2 (CNNM2) gene (Rose et al., 2014). The authors
did not find any association between the rs7914558 SNP and white mat-
ter volume. CNNM2 is a divalent metal cation transporter and may be
part of a proteomic network centered on CAv2.
Among schizophrenia GWAS genes, the microRNA-137 (MIR137)
gene may be of particular importance. A SNP just upstream of this gene,
rs1625579, demonstrated genome-wide significance and was the ‘top
hit’ after the MHC region in a recent GWAS that also included meta-
analysis (Ripke et al., 2013). MIR137 may be of particular importance, be-
cause it appears to relate intimately to other schizophrenia GWAS genes,
possibly suggesting a central or prominent role for this gene in disease ex-
pression. Of note, this microRNA has as its targets schizophrenia GWAS
genes CSMD1, C10orf26, CACNA1C, and TCF4 (Kwon et al., 2013), as
well as ZNF804A (Kim et al., 2012). Thus, MIR137 may act through
other schizophrenia GWAS risk genes. Since microRNAs regulate transla-
tion of other mRNAs they may affect phenotypic expression of disease.
Accordingly, this variant has been found to influence age-at-onset, hippo-
campal and lateral ventricle volume, and whole brain white matter FA in
people with schizophrenia, thus serving as an explanation for the hetero-
geneity of phenotypic expression of disease (Lett et al., 2013). Notably,
this variant was not significantly associated with structural neuroimaging
phenotypes in healthy individuals in the same study. Consistent associa-
tion of this variant with structural brain phenotypes in patients was
shown across the adult lifespan, where risk allele homozygotes had signif-
icant impairments in brain structure from the first episode of illness. This
study demonstrates that the consequences of risk variation may differ in
patient and healthy control groups, supported by a recent functional neu-
roimaging study (van Erp et al., 2014), with another study investigating
controls only (Mothersill et al., 2013). Furthermore, from a clinical stand-
point, the finding by Lett et al. raises the potential for disease prognostica-
tion and staging among patients with schizophrenia using a combination
of imaging and genetics. Overall, however, neuroimaging studies of
GWAS variants leave much to be desired. Many studies, despite their re-
cent publication dates, are using basic white matter volumetric pheno-
types rather than DTI-based phenotypes, and few studies are including
patients with schizophrenia.
In many ways the GWAS field in schizophrenia is still in its earliest
days. Most studies have been completed in Caucasians only. Sex effects
are rarely studied. Epistatic interactions between or among genes have
not yet been reported. Therefore, clarification and translatability to peo-
ple of other ethnic backgrounds and sex effects will be important future
directions, and subsequently can inform studies combining brain imag-
ing and genetics. For instance, in a Han Chinese sample, a genome-wide
significant SNP, from the vaccinia-related kinase (VRK2) gene,
rs2312146 was associated with white matter volume, and with up-
regulation in schizophrenia patients (Li et al., 2012). With respect to
sex, a GWAS study identified that the rs7341475 SNP in the reelin
gene (RELN), was associated with schizophrenia only in women
(Shifman et al., 2008). However, a comprehensive association study of
this SNP with brain structure (including DTI), function, and postmortem
tissue expression revealed no association with any of these phenotypes
either via main effect, or gene by sex interaction (Tost et al., 2010).
Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
6. Rare variants and highly penetrant mutations
The 22q11 deletion syndrome is reviewed in another manuscript in
this special issue. Genome-wide approaches also can identify genomic
deletions and duplications, i.e. copy number variation. Ideally a number
of subjects with a deletion or duplication in the same genomic region
can be collected for study, i.e. for ‘bottom-up’ phenotyping. However,
since it is so challenging to identify a sufficient number of individuals
with the same genomic change, a SNP with functional relevance in that
region could instead be used to understand effects of variation on white
matter phenotypes. For instance, deletions and duplications of genes in
the neurexin superfamily increase risk for schizophrenia (O'Dushlaine
et al., 2011). The contactin-associated protein-2 (CNTNAP2) gene, a
member of the neurexin superfamily is on chromosome 7 and has
shown associations with autism and schizophrenia. The rs271026 SNP
from CTNNAP2 was associated with FA in the uncinate fasciculus
(Clemm von Hohenberg et al., 2013). Another SNP in the same gene,
rs779475, was associated with FA in anterior thalamic radiation in fe-
males, and with FA of rostral fronto-occipital fasciculus in males. Similar-
ly, a SNP in neurexin1, rs1045881, located in the 3′ untranslated region of
the gene, and serving as a microRNA binding site, was associated with
frontal lobe white matter volume in healthy individuals (Voineskos
et al., 2011c). It remains unclear whether ‘tagging’ a genomic deletion
with a common genetic variant is a tractable approach; however due to
the high odds ratios conferred by a structural genetic change within
these susceptible regions, further exploration of susceptible genes in rela-
tion to white matter phenotypes is definitely warranted.
7. Multi/polygene approaches
Since several risk loci have only been discovered very recently, some
have not yet been examined in relation to neuroimaging phenotypes.
However, collaborative efforts, and a transition to polygenic, rather
than single variant-at-a-time investigations will likely change our
understanding of the effects of proven risk loci on white matter pheno-
types. Multivariate approaches such as independent components analy-
sis (ICA) and partial least squares (PLS) can be used to simultaneously
assess the relationship between a group of SNPs and a number of neuro-
imaging phenotypes. One recent paper (Voineskos et al., 2013a)
assessed the relationship of SNPs in oligodendrocyte and myelin genes
with FA of several white matter tracts both in healthy people and in
people with schizophrenia. Gene variants in MAG and CNP were
associated with fronto-temporal and interhemispheric white matter
tract FA. Furthermore, relationships of some of these SNPs with
neurocognitive performance were mediated through white matter FA.
A small study using parallel ICA explored the relationship of 367 SNPs
with optimized VBM data from MRI scans, but focused only on gray
matter. No white matter results were reported (Jagannathan et al.,
2010).
Perhaps the most straightforward approach for examining effects of
several gene variants was demonstrated in a recent study. The authors
pre-selected one SNP from each of 6 genes (Kohannim et al., 2012),
which had previously been associated with white matter FA (BDNF,
NTRK1, ErbB4, Clusterin (CLU) (Braskie et al., 2011), HFE, and COMT
(Thomason et al., 2010), and in this case used FA of the corpus callosum
as their main phenotype. The authors found that 5 of the 6 SNPs exam-
ined explained nearly 6% of the variability in mean callosal FA, using a
linear mixed effects model, and also displayed extensive, significant ef-
fects on 82% of the volume of the corpus callosum. In a somewhat differ-
ent approach, from a sample of 472 twins and their non-twin siblings
(Chiang et al., 2012), the authors used their sample to identify patterns
of brain regions where white matter FA was under strong and relatively
homogeneous genetic control. Then, they performed GWA from a num-
ber of ROIs to identify SNPs associated with FA in these regions. SNP
pairs were then discovered that tended to jointly affect brain regions.
Network topology analysis was then applied to this SNP association
 A.N. Voineskos / Schizophrenia Research xxx (2014) xxx–xxx
matrix and a SNP network that influences white matter integrity was
isolated. Hub SNPs in the network interacted with each other in their ef-
fects on white matter integrity, and possibly influenced intellectual per-
formance. SNPs from genes within a number of networks were
identified including cell adhesion, synapse, molecular functions, nerve
fiber integrity, and others.
Finally, another approach that takes the effects of multiple genetic
variants into consideration is the polygenic risk score, which is gaining
traction across different types of genetic studies of psychiatric disorders.
In a study examining shared susceptibility for schizophrenia and brain
volumes (Terwisscha van Scheltinga et al., 2013), odds ratios for
genome-wide SNP data were calculated from a sample of 8690 patients
and 11831 control subjects. This information was used to calculate indi-
vidual polygenic schizophrenia (risk) scores in an independent sample
of 152 patients and 142 controls with MRI data. The polygenic risk
score was significantly associated with white matter volume equally in
patients and control subjects. The polygenic schizophrenia score was spe-
cifically associated with reduced white matter volume but did not explain
variance in gray matter volume. While 14,751 SNPs modulated disease
risk (i.e. explained variance in disease status), a smaller subset of 2,020
SNPs explained most of the variance in white matter. From the set of
2020 SNPS, 186 showed most evidence for association with white matter
volume. Genes of these 186 SNPs were groupable into seven clusters,
with an immunoglobulin-like cell-adhesion molecule cluster as enriched
compared with the reference database.
8. Conclusion
A major challenge but also source of potential progress, is the iden-
tification of the genetic risk factors of disease as they pertain to the
brain structures or circuitry vulnerable in schizophrenia (Akil et al.,
2010). With heritability established, white matter FA is a reasonable
phenotype to study in schizophrenia, since many studies have found
FA reductions in patients, and intermediate FA reductions are present
in first-degree relatives. Most genetic association studies of white mat-
ter FA have used healthy participants only. Early studies used small
sample sizes, and only recently are large, and sometimes very large
(through the combination of data from different sites) samples being
used. Candidate gene studies were initially conducted, and the focus
has now moved to genetic variants with genome-wide significant evi-
dence for a role in schizophrenia. No specific neuroanatomic pattern
of association has emerged with any one of these genes, possibly due
to some studies hypothesizing (and examining) association with only
one or a small number of white matter tracts, while others have used
a ‘brain-wide’ approach with existing analytic tools such as TBSS.
Other white matter imaging techniques such as Magnetization Transfer
Ratio, which can better index myelin integrity compared to DTI, have
been underutilized in imaging-genetics studies. Advanced diffusion im-
aging techniques such as diffusion spectrum imaging, which can pro-
vide superior neuroanatomic characterization of brain white matter,
will be an important area of future investigation that the field of
imaging-genetics can benefit from.
Only a small number of imaging-genetic GWAS variant–white mat-
ter studies have examined association in patients. This is an important
issue, because gene systems may predict neural variation and behaviour
(cognition) in a different manner in a disease population compared to a
healthy population. That is to say that utilization of the intermediate
phenotype approach in a healthy population does not conclusively
prove how a gene variant might predict brain structure or function in
an individual with disease. Using imaging-genetic strategies in patient
populations should help provide biological clues regarding the consid-
erable heterogeneity of disease expression among people with schizo-
phrenia. (Gottesman and Gould, 2003; Meyer-Lindenberg and
Weinberger, 2006; Voineskos et al., 2013b). The collection of large
datasets now means that QTL approaches are now possible, where
genome-wide association with DTI-based phenotypes can be examined.
Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034
7
Little work has been done in this area to date, but the emergence of the
ENIGMA working group, and other working groups (e.g. B-SNIP,
IMAGEN), means that new genome-wide hits for association with
white matter FA are imminent. Similarly, polygenic analyses are now
possible, and results using such an approach are starting to emerge. Lit-
tle to no gene–gene interaction work has been done, unlike with fMRI
for instance (e.g. (Callicott et al., 2013), and this is an important area
of future investigation using white matter phenotypes. Acceleration in
bioinformatic approaches to functionally annotate the genome
(Bernstein et al., 2012; Birney, 2012) (e.g. ENCODE) facilitates opportu-
nities to understand the role of a risk locus at a molecular level. Publical-
ly available databases (e.g. BRAINCLOUD) (Colantuoni et al., 2011) offer
the opportunity to explore putative mechanistic effects of risk loci via
association with mRNA expression. The developing Allen Brain Atlas
documents gene expression in specific brain regions (Shen et al.,
2012)). Bridging the gap from gene to brain is now at our finger-tips.
Clinical translation is the ultimate goal. Using polygenic models of
risk prediction combined with neuroimaging, the field can begin mov-
ing toward disease risk prediction for high-risk adolescents or family
members in a clinical setting. However, prior to such tangible progress,
further clarification and work is needed to definitively establish the ‘in-
termediate findings’ in ultra high risk subjects, such that quantitatively-
based disease staging (i.e. preclinical vs. clinical) can occur accurately.
At the beginning of evident clinical disease expression (e.g. the first ep-
isode of psychosis), new findings suggest that imaging-genetic data
from carefully characterized patient samples could be used to aid in
prognosis (Lett et al., 2013). However, it will be useful to further clarify
genetic effects at different timepoints in the lifespan, such that investi-
gators can appropriately ‘hone in’ to use imaging-genetics to address
questions related to identifying disease risk (in childhood and adoles-
cence) and disease heterogeneity (in adulthood). Another important
area of clinical application is treatment innovation. With research prior-
ities at the National Institute of Mental Health moving toward a Re-
search Domain Criteria (RDoC) style approach (Insel et al., 2010),
brain circuits are becoming foci for therapeutic innovation. One could
envision a scenario in which, either prior to psychotic illness onset
(e.g. a high-risk state), or during illness, certain genetic risk carriers
are administered a specific treatment. If the gene (or genes) in those in-
dividuals predisposes to vulnerability or impairment in a specific circuit
that is relevant to a specific behavioral impairment, e.g. prefrontal inter-
hemispheric impairment and working memory impairment, then treat-
ment response could be assessed via early changes in circuit structure or
circuit function. The addition of genetically mediated differences in cir-
cuit structure and function will be an important component of such in-
novation. Overall, this field is moving rapidly, and replicable discoveries
are starting to be made. Given that schizophrenia is a brain disease, and
that genomic discoveries are beginning to translate into therapeutic
progress in other areas of medicine, it should only be a short matter of
time before imaging-genomics does the same for schizophrenia.
Role of the funding source
None of the funders played any role in the design, conceptualization, or writing of the
manuscript.
Contributors
Dr. Voineskos designed, conceptualized, and wrote the manuscript.
Conflict of interest
Dr. Voineskos has no conflicts of interest to disclose. He would like to acknowledge
funding from the Canadian Institutes of Health Research, Ontario Mental Health Founda-
tion, Brain and Behavior Research Foundation, National Institute of Mental Health
(R01MH099167), and the Koerner, Labatt, and Kimel Families via the CAMH Foundation.
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Please cite this article as: Voineskos, A.N., Genetic underpinnings of white matter ‘connectivity’: Heritability, risk, and heterogeneity in
schizophrenia, Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.03.034