The following list is not intended to be comprehensive.
Gothelf, D et al. Obsessive-compulsive
disorder in patients with velocardiofacial (22q deletion)
syndrome. American Journal of Medical Genetics Part
B (Neuropsychiatric Genetics) 126B: 99-105 (2004)
In response to their clinical experience indicating
that many patients with velocardiofacial syndrome (VCFS)
have debilitating obsessive-compulsive symptoms, as well
as previous research supporting obsessive-compulsive
disorder (OCD) as part of the behavioral phenotype, the
authors evaluated the prevalence of OCD in 43 individuals
with VCFS. The sample consisted of 25 males and
18 females, ages 6-40 years. Fourteen of the individuals
(32.6%) met the DMS-IV criteria for OCD. At least
one symptom of obsession or compulsion was found in 35
patients (83%). The authors found that the OCD
had an earlier age at onset than is usual, responded
well to treatment, and was not related to mental retardation. The
authors reported a risk for OCD in individuals with VCFS
that was increased two- to four-fold over previous studies;
the authors hypothesize that this is because OCD was
the focus of their study and more sensitive screening
instruments were used.
Other disorders found in the VCFS sample included 16
patients with ADHD, inattentive and combined types (37%);
nine patients had dysthymic disorder (21%); and 7 patients
with psychotic disorders, including schizophrenia, schizoaffective
disorder, and psychotic depression (16%). The mean
number of psychiatric diagnoses per patient was 2.6 ± 1.7.
Only 3 of the 43 patients had no psychiatric disorder. Six
of the 43 cases were familial.
Limitations of the study include a small sample size
and the lack of a control group.
Back to the top
Caspi, A. et al. Influence of
life stress on depression: moderation by a polymorphism
in the 5-HTT gene. Science 301: 386-389 (2003)
This prospective-longitudinal study of a representative
birth cohort examined why depression develops in some
people exposed to stressful experiences, but not in others. This
study found that individuals with one or two copies of
the short allele of a serotonin transporter gene (5-HTT)
promoter polymorphism had more depressive symptoms, diagnosable
depression, and suicidality when compared to individuals
with two copies of the long allele. The study population,
consisting of 847 Caucasian individuals, was divided
into three groups based on their genotype: homozygous
for the short allele, heterozygous, and homozygous for
the long allele. After assessing the individuals’ stressful
life events, they found that the effect of life events
on self-reports of depressive symptoms at age 26 was
significantly stronger among those with either one or
two copies of the short allele, as compared to those
with two copies of the long allele. In those with
one or two copies of the short allele, suicide ideation
or attempt could be predicted by stressful life events,
but not in those without the short allele. Also,
childhood maltreatment was found to be a predictor of
adult depression in those carrying a short allele but
not in those without the short allele. This paper
provides evidence of a gene-environment interaction in
which an individual’s genes moderate his or her
response to environmental stressors. The interaction
of this polymorphism and life events proved to be predictive
of depression at the age of 26 years. The authors point
out that it is possible that some mutifactorial disorders
may actually be a result of fewer genes, the effects
of which are dependent on exposure to environmental stressors. These
findings (if replicated) also may lead to the development
of better pharmacological treatments for those who are
depressed, as over half of the Caucasian population carries
a short allele.
Back to the top
Hattori, E et al. Polymorphisms
at the G72/G30 gene locus, on 13q33, are associated
with bipolar disorder in two independent pedigree series.
American Journal of Human Genetics 72: 1131-1140 (2003)
Previously published data provide evidence that chromosome
13 (13q32-33) contains susceptibility genes for both
bipolar disorder and schizophrenia. Other recently
published data identified two genes, “G72” and “G30” at
this same locus, and provided evidence that they are
associated with schizophrenia. Hattori et al. examined
two series of pedigrees with bipolar disorder- Clinical
Neurogenetics pedigrees and National Institute of Mental
Health Genetics Initiative pedigrees. Sixteen SNPs
at and around the G72/G30 locus were genotyped in the
two series of pedigrees. Using transmission/disequilibrium
testing (TDT) and haplotype analysis, they provide data
that suggest a susceptibility allele for bipolar disorder
in the area of the G72/G30 genes. This is the first
demonstration of identifying novel genes independently
associated with both bipolar disorder and schizophrenia
using a positional approach.
Back to the top
Hudson, J.I. et al. Family study
of affective spectrum disorder. Archives of General
Psychiatry 60: 170-177 (2003)
Developed from a pharmacologic treatment-response model,
the affective spectrum disorder (ASD) hypothesis suggests
that 14 various psychiatric and medical disorders share
a common and possibly heritable pathophysiologic basis. This
article tests two predictions based on this hypothesis:
1) ASD (as a single entity) aggregates in families, and
2) major depressive disorder (MDD) coaggregates with
other forms of ASD in families. Forms of ASD include
MDD, attention-deficit/hyperactivity disorder, bulimia
nervosa, cataplexy, dysthymic disorder, fibromyalgia,
generalized anxiety disorder, irritable bowel syndrome,
migraine, obsessive-compulsive disorder, panic disorder,
posttraumatic stress disorder, premenstrual dysphoric
disorder, and social phobia. A family interview
study was performed in 178 interviewed relatives of 64
probands with MDD, and in 152 interviewed relatives of
58 nondepressed control probands. Their findings
were consistent with the ASD hypothesis, with an estimated
odds ratio for the familial aggregation of ASD, as a
single entity, of 2.5 and for the familial coaggregation
of MDD with at least one other form of ASD of 1.9. These
findings support the theory that various forms of ASD
may share a heritable physiologic abnormality, which
may have important clinical and therapeutic implications. The
authors do suggest alternative possibilities to explain
their findings (such as ascertainment bias or environmental
factors). However, none offer compelling evidence
against the predictions of the ASD hypothesis.
Back to the top
McMahon, W.M. et al. Children
at familial risk for Tourett’s disorder: child
and parent diagnoses. American Journal of Medical
Genetics Part B (Neuropsychiatric Genetics) 121B: 105-111
(2003)
This current prospective longitudinal study examines
the onset of Tourett’s disorder (TD) in offspring
of parents with TD. At-risk children (defined as
having at least one parent diagnosed with TD) and control
children between 3 and 6 years of age were enrolled. They
were prospectively studied over 2 to 5 year intervals,
with structured assessments every year. The results
show that children at risk for TD have higher rates of
TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity
(ADHD) when compared to controls. In addition,
the at-risk families were divided into bilineal (both
parents affected with TD) and unilineal (one parent affected
with TD) groups. Rates of tics, ADHD, combined
tics/OCD, and combined tics/OCD/ADHD diagnoses were all
significantly increased in the bilineal group. McMahon
et al. had previously found that children with both parents
affected had an earlier age of onset then those with
one affected parent; this study did not support those
earlier findings, as there was not a significant difference
in the age of onset between the bilineal and uilineal
groups. The authors point out the small sample
size of the control group (n=13) compared to the at-risk
group (n=34). In addition, the mean age of both
groups was young (7.3 years in the at-risk group and
5.9 years in the control group). The authors conclude
that their findings support the hypothesis that some
cases of TD are due to a complex genetic etiology. However,
they do not exclude the possibility of important environmental
factors (such as streptococcal infections).
Back to the top
Philibert, R et al. The association
of the D2S2944 124 bp allele with recurrent early onset
major depressive disorder in women. American Journal
of Medical Genetics 121B: 39-43 (2003)
This paper replicated results from a previous publication
that the 124 bp allele of D2S2944, a tetranucleotide
repeat marker of 2q35, is strongly associated with recurrent,
early onset major depressive disorder (RE-MDD) in women. They
studied this association in a subset of the Iowa Adoption
Studies population that included high rates of MDD and
substance use disorders (SUD). In addition to confirming
the statistically significant association between the
D2S2944 allele and RE-MDD in women, the authors also
studied possible associations with various categories
of SUD. (Previously published data also provided
evidence for an association between the 124bp allele
and alcohol use disorders in women.) This study
did not confirm that finding, but data suggest an association
with cannabis use disorders. The authors suggest
that, after independent replication, a haplotype map
should be constructed and the region should be re-sequenced.
Back to the top
Tkachev, D et al. Oligodendrocyte
dysfunction in schizophrenia and bipolar disorder. The
Lancet 362:798-805 (2003)
Tkachev et. al. investigated the relationship of oligodendrocyte-specific
and myelination-associated gene expression with schizophrenia
and bipolar affective disorder. Using indexing-based
differential-display PCR, human schizophrenia, bipolar,
and control brain samples were screened for differences
in gene expression. Quantitative PCR and microarray
analysis were used to confirm the findings. The
expression of several myelin-related protein genes were
found to be downregulated in both the schizophrenia and
bipolar samples (compared to control samples). These
included: proteolipid protein 1 (PLP1), myelin-associated
glycoprotein (MAG), oligodendrocyte-specific protein
(CLDN11), and myelin oligodendrocyte glycoprotein (MOG). The
expression of myelin basic protein (MBP) was also found
to be downregulated in the schizophrenia group, but remained
unchanged in the bipolar group. In addition, the
expression of several oligodendrocyte-specific genes
(including transcription factors) were also found to
be downregulated in both the schizophrenia and bipolar
groups. These included: ERBB3, transferrin (TF),
OLIG2, and SOX10. The expression of GALC was found
to be downregulated in the bipolar group, remaining unchanged
in the schizophrenia group, while OLIG1 was found to
be downregulated in the schizophrenia group but unchanged
in the bipolar group. Interestingly, even though
neuregulin 1 (NRG1) has been identified as a candidate
gene for schizophrenia, its expression remained unchanged
when compared to the control group. The expression
of platelet derived growth factor receptor alpha (PDGFRA)
and NG2 proteoglycan genes also remained unchanged. These
results support that key oligodendrocyte and myelination
genes, including transcription factors involved in regulation,
are downregulated in schizophrenia and bipolar brains,
compared to control samples. However, the question
remains as to whether these changes are disease-specific,
due to a “sick-brain event,” or if they are
secondary to another disease process.
Back to the top
Stefansson H et al. Neuregulin
1 and susceptibility to schizophrenia.
American Journal of Human Genetics 71: 877-892 (2002)
This paper reports results from a genomewide scan and
resulting fine-mapping of schizophrenia families in Iceland. The
genome scan identified 8p as a region likely to harbor
a susceptibility gene; this region has previously been
identified by several other groups. Fine mapping
of 8p identified neuregulin 1 as a candidate
gene for schizophrenia. The paper discusses the
biological plausibility of this gene, including data
from mutant mice strains.
Back to the top
Smalley, SL et al. Genetic linkage
of attention deficit/hyperactivity disorder on chromosome
16p13, in a region implicated in autism. American Journal
of Human Genetics 71: 959-964 (2002)
This paper expands on results from the author’s
first genome-wide scan of ADHD, and reports the first
significant linkage result in ADHD. Using sib-pair
analysis the group located a 12-cM region of 16p13 that
yielded a maximum LOD score of 4.2. This region
overlaps with those highlighted in three genome scans
for autism. The authors state that additional investigation
is needed to determine whether the implicated region
contains a risk gene for ADHD, autism, or both disorders.
Back to the top
Caspi, A; McClay, J; Moffitt,
TE; Mill, J; Martin, J; Craig, IW; Taylor, A, and Poulton,
R. Role of genotype in the cycle of violence
in maltreated children. Science 297: 851-854 (2002)
The group studied a large cohort of adult males from
New Zealand to determine why childhood maltreatment affects
different individuals differently. This study is
especially interesting because the researchers tested
for the effect of the interaction between a gene and
an environmental factor. The group studied a functional
polymorphism in the gene encoding the neurotransmitter-metabolizing
enzyme monoamine oxidase A (MAOA). They
found that over 85% of individuals who had low levels
of MAOA and who had experienced maltreatment
as a child developed some sort of antisocial behavior
by age 26.
Back to the top
Weiser, M. et al. Clinical
characteristics of adolescents later hospitalized for
schizophrenia. American Journal of Medical Genetics
114: 949-955 (2002)
Weiser et al. present a prospective study on a population-based
cohort of male adolescents to evaluate intellectual and
behavioral abnormalities in adolescents who later developed
schizophrenia. Medical and physical assessments
of 16- and17-year-old males screened by the Israeli Draft
Board were cross-linked with the National Psychiatric
Hospitalization Case Registry. A paired samples t-test
was used with 509 individuals who later developed schizophrenia
and with matched control schoolmates. As a group, those
who later developed schizophrenia obtained significantly
lower scores on all measures of baseline intellectual
and behavioral functioning, as compared to the matched
controls and to the entire population (P<0.0001 for
all measures). The greatest difference was seen
in the social functioning scores. In addition,
26.8% of the males hospitalized for schizophrenia suffered
from non-psychotic psychiatric disorders in adolescence,
as compared to 7.4% in the general population of adolescents. More
specifically, the adolescent males with anti-social personality
disorder, mental retardation, or drug abuse had an Odds
Ratio (OR) in the range of 7-9, and those with schizophrenia
spectrum personality disorders had an OR of 21.5. Weiser
et al. also examined the role of drug abuse, consisting
mostly of marijuana. Those adolescents who self-reported
abuse of drugs at ages 16 to17 were 2 times more likely
to be hospitalized for schizophrenia later. The
authors report that the drug abuse was not found to be
consistent with self-medication of pre-morbid symptoms. This
study supports and expands on the findings of previously
published literature that find subtle impairments in
intellectual and behavioral functioning in those who
later develop schizophrenia.
Back to the top
Palmer, C.G. et al. RHD
maternal-fetal genotype incompatibility increases schizophrenia
susceptibility. American Journal of Human Genetics
71: 1312-1319 (2002)
Previous studies have implicated Rh incompatibility
as a risk factor for schizophrenia. An estimated
overall odds ratio of 2.0 has been reported for the association
between Rh incompatibility and schizophrenia. Palmer
et al. report on a family-based candidate-gene study
that investigated the role of maternal-fetal genotype
incompatibility at the RHD locus in schizophrenia. They
provide evidence that the RHD locus does not increase
the risk of schizophrenia through linkage/association
with the disorder, linkage disequilibrium with a nearby
susceptibility locus, or a direct maternal effect alone. Instead,
this is the first study that provides evidence that the
risk of schizophrenia is increased through a maternal-fetal
genotype incompatibility mechanism. 450 Finnish
individuals, consisting of 88 patient-parent trios, 72
patient-mother pairs, and 21 patient-father pairs, were
studied. The study found that the relative risk
of RHD maternal-fetal genotype incompatibility acting
alone is 2.26. They explain that even in the presence
of prophylaxis, incompatibility of RHD maternal-fetal
genotype may remain a risk factor for schizophrenia. Further
research is warranted.
Back to the top
