NIH Public Access Author Manuscript MANEA Behaviors

NIH Public Access Author Manuscript MANEA Behaviors
NIH Public Access
Author Manuscript
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
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Published in final edited form as:
Arch Gen Psychiatry. 2009 March ; 66(3): 267–274. doi:10.1001/archgenpsychiatry.2008.538.
Association of Variants in MANEA With Cocaine-Related
Behaviors
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Lindsay A. Farrer, PhD, Henry R. Kranzler, MD, Yi Yu, MSc, Roger D. Weiss, MD, Kathleen T.
Brady, MD, PhD, Raymond Anton, MD, Joseph F. Cubells, MD, PhD, and Joel Gelernter, MD
Departments of Neurology, Genetics & Genomics, Epidemiology, and Biostatistics (Dr Farrer), and
Medicine, Genetics Program (Drs Farrer and Yu), Boston University Schools of Medicine and Public
Health, Boston, Massachusetts; Department of Psychiatry, University of Connecticut School of
Medicine, Farmington (Dr Kranzler); Alcohol and Drug Abuse Treatment Program, McLean Hospital,
Belmont, Massachusetts (Dr Weiss); Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina, Charleston (Drs Brady and Anton); Department of Human Genetics,
Emory University School of Medicine, Atlanta, Georgia (Dr Cubells); Department of Psychiatry,
Division of Human Genetics, and Departments of Neurobiology and Genetics, Yale University
School of Medicine, New Haven, Connecticut; and VA Connecticut Health-care System, West
Haven (Dr Gelernter)
Abstract
Context—Cocaine dependence (CD) and related behaviors are highly heritable, but no genetic
association has been consistently demonstrated. A recent genome-wide study of drug dependence
identified an association between cocaine-induced paranoia (CIP) and a single-nucleotide
polymorphism (SNP) in the α-endomannosidase (MANEA) locus in a family-based sample of
European Americans and African Americans.
Objective—To conduct a comprehensive genetic association study of the MANEA locus with CD
and CIP.
Design—Genome-wide association study.
Setting—Four university hospitals.
Participants—A total of 3992 individuals from 2 family-based and 2 case-control samples.
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Intervention—Participants were classified as having CD or CIP or as a control using the SemiStructured Assessment for Drug Dependence and Alcoholism. They were genotyped for 11 SNPs
spanning MANEA and its surrounding region.
Main Outcome Measure—Association of CD and CIP with individual SNPs and haplotypes.
Correspondence: Lindsay A. Farrer, PhD, Genetics Program, Boston University School of Medicine, L320, 715 Albany St, Boston,
MA 02118 ([email protected])..
Author Contributions: Study concept and design: Farrer, Kranzler, and Gelernter. Acquisition of data: Kranzler, Weiss, Brady, Anton,
Cubells, and Gelernter. Analysis and interpretation of data: Farrer, Yu, and Gelernter. Drafting of the manuscript: Farrer. Critical revision
of the manuscript for important intellectual content: Farrer, Kranzler, Weiss, Brady, Anton, Cubells, and Gelernter. Statistical
expertise: Farrer and Yu. Obtained funding: Farrer, Kranzler, Weiss, Brady, Cubells, and Gelernter. Administrative, technical, or material
support: Farrer, Kranzler, Weiss, Brady, and Gelernter. Study supervision: Farrer, Kranzler, and Gelernter.
Additional Contributions: We are indebted to Clinton Baldwin, PhD, for critically evaluating the manuscript and Kevin Jensen, BS,
for discussions about microRNA. Ann Marie Lacobelle, MS, Michelle Streckenbach, BA, and Gregory Dalton-Kay, BA, provided
excellent technical assistance. John Farrell, MS, and David Johnson, BA, provided expert database management services. We thank the
individuals who participated in this research study and the interviewers who administered the Semi-Structured Assessment for Drug
Dependence and Alcoholism to those participants.
Financial Disclosure: None reported.
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Results—Cocaine-induced paranoia was associated with 6 SNPs in the European American
families and 9 SNPs in the African American families. The strongest evidence in the total sample of
families was observed in 3 markers located in the promoter and 3′ untranslated regions (P < .001).
The association of MANEA SNPs with CD in both family samples was much weaker. In the African
American case-control sample, multiple markers were significantly associated with CIP and CD;
CIP and CD were also significantly associated with a 2-SNP haplotype in the European American
case-control sample. The A allele of the 3′ untranslated region SNP rs9387522 was associated with
increased risk of CIP in all 4 data sets.
Conclusions—Our findings suggest that CD and associated behaviors may involve biological
pathways not typically thought to be associated with brain metabolism.
COCAINE IS WIDELY USED IN the United States. The 2002 National Survey on Drug Use
and Health revealed that nearly 6 million Americans aged 12 years or older used the drug during
the preceding year, making cocaine second only to cannabis as the most commonly used illicit
drug.1 Compulsive use of cocaine is also common, with more than 1 million individuals
meeting criteria for dependence on the drug.1 Cocaine dependence (CD) is associated with
criminal behavior and accidental injury and spans geographical region, race and ethnicity, and
socioeconomic status.
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Vulnerability to the development of CD varies among individuals. Adoption, twin, and family
studies show a substantial genetic contribution to CD.2-6 Identification of genes that influence
CD susceptibility could help elucidate the etiology of the disorder and provide critical insight
to develop efficacious treatments. Reports of genetic associations for CD derive mostly from
relatively small samples,7-9 resulting in limited capacity for replication.10-13 Evidence for
multiple subtypes of CD14,15 makes it possible to decompose the broader set of those with CD
into phenotypic subgroups, thereby reducing the genetic heterogeneity of the sample and
increasing the likelihood of identifying a particular genetic factor that contributes to risk. Most
(up to 60%-80%) long-term cocaine users experience transient psychotic symptoms, such as
paranoia and hallucinations, that typically resolve with abstinence.16-18 Cocaine-induced
paranoia (CIP) appears to represent a reliably identifiable phenotype that reflects
interindividual differences in the brain's response to cocaine.18 Cocaine-induced paranoia has
important clinical and public health significance, since, in addition to being highly prevalent,
it appears to pre-dispose individuals to a number of high-risk behaviors, including accidents,
self-harm, and violence toward others.19,20
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A genome-wide linkage scan detected regions that harbor genes for CD on chromosomes 3
and 10, and for CIP on chromosome 9,21 but no genes under these linkage peaks have yet been
identified as risk loci for either condition. Moreover, studies targeting candidate genes selected
because of inferred roles in cocaine metabolism or compulsive use have not yielded confirmed
associations for CD or CIP, though there are several previous reports of CIP's association with
dopamine-pathway genes.22,23 Recently, we conducted a genome-wide association study using
a low-density SNP array for 6 traits corresponding to 4 major substance dependence disorders
(including CD) in a family-based cohort that included 2 distinct population groups. The most
remarkable result was an association of a single-nucleotide polymorphism (SNP), rs1133503,
in the 3′ untranslated region (UTR) of the MANEA gene (GenBank 79694) with CIP in
European American (EA) families (P=.007), African American (AA) families (P=.002), and
all families combined (P>.001).24 Although this result was not significant after adjustment for
multiple comparisons, the hypotheses that were generated prompted a more comprehensive
association study of this gene with cocaine-related traits in 2 discovery data sets (EA and AA
families) and 2 independent EA and AA replication data sets composed of unrelated cases and
controls ascertained for studies of alcohol and drug dependence.
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METHODS
SUBJECTS
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Subjects were recruited from Yale University School of Medicine (APT Foundation, New
Haven, Connecticut), the University of Connecticut Health Center (Farmington), McLean
Hospital (Harvard Medical School, Belmont, Massachusetts), and the Medical University of
South Carolina (Charleston) into 1 of 2 study arms. Six hundred thirty-two families ascertained
through affected sibling pairs that met DSM-IV criteria for CD or opioid dependence as
previously described,15,21,25 containing at least 1 examined sibling with CD or CIP, formed
the discovery sample. Of the 632 families, 119 had at least 1 sibling pair discordant for CD
and 319 had at least 1 sibling pair discordant for CIP. Of the 1612 genotyped subjects, 160
were parents (9.9%) (and the remainder were siblings) and 141 did not contribute information
about substance dependence (8.7%). An independent group of 2073 unrelated subjects
recruited for studies of CD (n=667), opioid dependence (n=103), or alcohol dependence
(n=1303) were included in a replication sample. Genetic studies of CD and related traits in a
subset of this sample have been published.10,23
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All subjects were interviewed using the Semi-Structured Assessment for Drug Dependence
and Alcoholism, which has been shown to yield reliable substance dependence diagnoses.21,
26 Subjects with a primary diagnosis of a major psychotic illness (schizophrenia or
schizoaffective disorder) were excluded. A diagnosis of CD was established if the subject met
3 or more of the 7 DSM-IV criteria during a 12-month period. The interrater reliability of the
Semi-Structured Assessment for Drug Dependence and Alcoholism diagnosis of CD was
previously shown to be κ=0.83.21 Subjects who gave an affirmative answer to the question,
“Have you ever had a paranoid experience when you were using cocaine?” were diagnosed as
being affected by CIP. The overall reliability of CIP diagnosis was previously shown to be
excellent (κ=0.87).21 Controls did not use cocaine, but individuals who had dependence on
other substances were included. Probands were excluded from further study if they had a
diagnosed major psychotic illness (eg, schizophrenia or schizoaffective disorder). Subjects
who had missing responses to items on the Semi-Structured Assessment for Drug Dependence
and Alcoholism that were required for the determination of CD or CIP status were also
excluded.
Subjects gave informed consent as approved by the institutional review board at each clinical
site. A certificate of confidentiality for the work was obtained from both the National Institute
on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. Characteristics
of both samples included in this study are given in Table 1.
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SNP SELECTION AND GENOTYPING
Eleven SNPs spanning 83 kilobases (kb) upstream of the MANEA promoter to downstream of
the MANEA 3′ UTR were selected from the National Center for Biotechnology Information
database or by the Applied Biosystems SNPbrowser, version 3.5 (Applied Biosystems, Foster
City, California). Characteristics of each SNP are presented in Table 2. The average intermarker
distance is 8295 base pairs (bp) for all SNPs, but only 5600 bp for the 7 SNPs in the promoter
and coding regions. Most SNPs were genotyped with a fluorogenic 5′ nuclease assay method,
ie, the TaqMan technique,27 using the Applied Biosystems PRISM 7900 Sequence Detection
System. One SNP (SNP 8) was genotyped in the family sample at the Center for Inherited
Disease Research as part of the Illumina Linkage IVb Marker Panel
(http://www.cidr.jhmi.edu).
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POPULATION CLASSIFICATION
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Subjects in the family-based sample were classified as AA or EA based on a Bayesian modelbased clustering method as previously described28 using approximately 400 short tandem
repeat markers and more than 5000 SNP markers from the Illumina Linkage IVb Marker Panel.
The race and ethnicity of subjects in the replication sample were self-identified. The genetic
backgrounds of nearly two-thirds of these subjects were also analyzed with the Bayesian
approach using a set of 180 ancestry informative markers. One hundred nineteen subjects in
the replication sample who self-reported their ethnicity as something other than AA or EA and
lacked ancestry informative marker data were excluded from further analysis. This resulted in
a final replication sample of 1921 subjects. The AA and EA population groups were treated as
independent samples for all primary analyses.
STATISTICAL ANALYSIS
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Consistency with Hardy-Weinberg equilibrium expectations for each SNP was examined with
the χ2 test in each discovery sample, using a set of unrelated subjects without CD (1 random
unaffected subject from each family), and in each of the control groups from the replication
sample. Two SNPs (rs9400554 and rs6937479) with significant evidence of deviation from
Hardy-Weinberg equilibrium (P>.001) in the AA replication sample were excluded from
analyses of allelic and genotypic association in that data set. In the family samples, mendelian
inheritance of all genotypes was evaluated using PedCheck,29 and pairwise marker linkage
disequilibrium was examined using the Haploview program, version 4.0.30 Association of the
MANEA SNPs with CD and CIP in the family samples was evaluated using the FBAT program,
31 assuming an additive model under the null hypothesis of no linkage and no association.
Allele frequencies were estimated by FBAT using the expectation-maximum algorithm. In the
case-control samples, a χ2 test was used to examine the association of SNP alleles and
genotypes with cocaine-related traits. Odds ratios and their 95% confidence intervals for the
allelic associations were computed using logistic regression analysis. Odds ratios were
unaffected by adjustment for age and sex. In these analyses, controls were compared with
distinct case samples of subjects with CIP and subjects with CD who did not have CIP.
Haplotype association analyses were performed in the family samples using HBAT, the
haplotype extension routine in the FBAT program,32 and in the case-control samples using
haplo.stats.33
RESULTS
FAMILY-BASED ANALYSES
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In the EA family sample, 6 of the 11 markers, including rs1133503 from the genome scan,24
showed at least a nominally significant association with CIP (Table 3). These 6 markers and
3 others were also significant in the AA family sample. The patterns of association were
identical in the 2 population groups for all 9 markers (which represent all markers tested in the
promoter and coding regions), evidenced by increased significance in the total sample of
families. The strongest evidence for association in either population (AA, P<.001) and in the
total sample (P<.001) was observed with rs6937479, which is located in the putative promoter
region. The association of MANEA SNPs with CD was much weaker. In the EA families,
nominally significant results were obtained with rs9374586 (P = .01), rs1133503 (P = .04),
and rs9387522 (P = .03). Although no significant associations were obtained in the AA
families, trends were evident in that population for several markers. Eight markers (rs9400554,
rs9320497, rs6937479, rs9374586, rs9400893, rs1133503, rs9387522, and rs9387605) were
nominally associated with CD in the total group of families (.007≤P≤.03).
Haplotype analysis was conducted in the family samples to help narrow the location of a CIP
susceptibility locus and to determine whether a single functional variant could explain the
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pattern of association findings with individual SNPs in each population group. As a first step,
we evaluated linkage distribution among the 11 SNPs to reduce the number of potentially
informative markers for haplotype analysis. This analysis, shown in the Figure, revealed
slightly more extensive linkage distribution in EAs than in AAs. These population-specific
patterns are consistent with the linkage distribution structures reported in the HapMap database
for this genetic region.34 Taking into account the linkage distribution block structure and the
association findings with individual SNPs, we selected 3 SNPs (rs9400554, rs6937479, and
rs9387522) for haplotype analysis. These markers include the 2 most significant results in the
combined sample and account for the potentially uniquely important information from each
linkage distribution block spanning the entire region, showing significance with any marker
in either population sample. The haplotype that included this SNP combination was
significantly associated in AAs (global, P=.003), EAs (global, P=.02), and the combined
sample of families (global, P=.001). The specific haplotype T-T-A was associated with CIP
in EAs (P=.01) and AAs (P=.02), and in the pooled sample (P<.001). Haplotype C-A-C was
associated with decreased risk of CIP in EAs (P=.01) and AAs (P<.001), and in the total sample
(P<.001). These 2 haplotypes account for 86% and 73% of all haplotypes in the EA and AA
families, respectively. A third haplotype (C-T-A), which had appreciable frequency in both
EAs (6%) and AAs (23%), was also associated with increased risk of CIP. Because both
rs9400554 alleles were part of different risk haplotypes, the functional variant is more likely
to be closer to the other 2 SNPs. Thus, these results, showing strong evidence for association
of the same haplotype to CIP in 2 distinct populations, support the existence of a single
causative variant that is most likely located in the MANEA promoter or coding region.
CASE-CONTROL ANALYSIS
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We evaluated the panel of MANEA SNPs in the EA and AA case-control samples in an attempt
to replicate the overall association with cocaine-related traits, to determine whether or not the
association is specific to CIP, and to localize the putative biological variant. In the AA
replication sample, significant association at the allelic and/or genotypic level was observed
between CIP and 5 markers (Table 4). These SNPs and a sixth marker were also associated
with CD in the absence of CIP. The strongest and most consistent evidence for association was
observed with adjacent markers rs9387522 and rs9387605. In the EA replication sample, the
only significant association was found for rs4388292 with CIP, which is accounted for
primarily by an underrepresentation of the TT genotype in CIP cases compared with controls.
The TT genotype is interestingly also significantly lower in individuals with CD compared
with controls in the AA replication sample. Although the results of analyses of individual SNPs
did not show an association common to both population groups, haplotype analysis of rs900554
and rs9387522 (ie, 2 of the 3 SNPs included in the haplotype studies in the families) showed
that the C-A haplotype was significantly associated with increased risk of CIP and CD in EAs
and that the T-A haplotype was significantly associated with CD in AAs (Table 5). The rare
T-C haplotype was also associated with increased risk of CD in EAs. Of note, when considering
results from both the single SNP and haplotype analyses in the replication samples, the
rs9387522 A allele is associated with CIP in all 4 data sets.
COMMENT
We observed that several polymorphic markers in the MANEA gene region are associated with
cocaine-related traits in 2 EA and 2 AA populations, which were ascertained and analyzed in
different ways. The strongest evidence was obtained for CIP with markers in the MANEA
coding and promoter regions, spanning a distance of approximately 33.6 kb (ie, between
rs9320497 and rs9387522). Haplotype analysis in the replication data sets helped confirm that
the rs9387522 A allele is associated with increased risk of CIP in all 4 populations. This SNP
is only 348 bp from rs1133503, the marker in the low-density genome scan that showed an
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association with CIP in the EA and AA family-based samples,24 which prompted this
investigation. Our comprehensive analysis of MANEA SNPs and haplotypes in 4 independent
data sets bolsters our initial association finding and indicates that the biologically relevant
variant is most likely located in the 3′ UTR.
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The results for association of MANEA with CD were substantially weaker in the discovery
(family-based) data sets. However, these samples were ascertained through sibling pairs with
CD or opioid dependence. They are, thus, much less informative for association analyses of
these traits compared with those with CIP, because, in the absence of data from parents, the
family-based approach requires at least 1 discordant sibling pair. To determine whether the
association with MANEA is specific to the paranoia that often complicates CD, we compared
MANEA SNPs and haplotypes in controls with distinct samples of subjects with CD (but no
paranoia) and subjects with CIP. In the AA group, CD and CIP were significantly and
comparably associated with several SNPs. Both traits showed identical patterns of association
with a particular haplotype in the EA group. Thus, our study suggests that MANEA is associated
with both CD and paranoia. It is also possible that MANEA is more strongly associated with
CIP than CD because CIP is characteristic of a genetic subgroup of CD that is influenced by
MANEA. Additional studies in independent samples of subjects with CD characterized for
paranoia, and perhaps in subjects with other disorders involving paranoia, are necessary to
determine more definitively whether the association with MANEA is specific for the subset of
persons with CD prone to CIP.
α-Endomannosidase (MANEA), encoded by the MANEA gene on chromosome 6q16.1, is an
enzyme that catalyzes the release of glucosyl-mannose oligosaccha-rides by cleaving the
α-1,2-mannosidic bond that links them to high-mannose N-glycans.35 Comparative genomic
analysis has demonstrated high-sequence conservation in humans, rats, and mice.36 Human
MANEA is expressed in a variety of tissues including brain, though levels of MANEA in the
brain are much lower than, for example, in the liver or kidney.36 The role of MANEA is poorly
understood but has been hypothesized to be involved in the quality control of N-glycosylation,
37 providing cells with the ability to recover and properly mature glucosylated structures that
have bypassed glucosidase trimming by glucosidases I and II in the endoplasmic reticulum.36
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Given MANEA's role in carbohydrate metabolism and its relatively minor expression in brain,
initially it would not appear to be a good biological candidate to modulate susceptibility to CD
or its associated psychotic complications. However, insight into the relationship between
MANEA, paranoia, and CD can be gleaned from studies of mannosidase and other
glycoproteins. α-Mannosidosis in humans is a rare autosomal recessive lysosomal storage
disorder associated with decreased activity of mannosidase. Recently, α-mannosidosis was
identified as the underlying cause of recurrent paranoid hallucinatory episodes in a 27-yearold woman.38 α-Endomannosidase is 1 of several glycosidic enzymes that remove
oligosaccharide chains of dopamine β-hydroxylase,39 the enzyme that converts dopamine to
norepinephrine. Low levels of β-hydroxylase in plasma or cerebrospinal fluid and
polymorphisms in β-hydroxylase have been associated with greater vulnerability to psychotic
symptoms in several psychiatric disorders including CD,23,40 schizophrenia,41 and major
depression.42 α-Endomannosidase may also influence susceptibility to CD by modifying the
function of liver carboxylesterase, a glycoprotein of the high mannose type,43 2 forms of which
hydrolyze cocaine and other drugs.44,45
There are 44 markers in MANEA with appreciable frequency in 1 or more populations
(http://www.ncbi.nlm.nih.gov/SNP), but none are known to effect structural changes in the
translated protein. Remarkably, 34 of these SNPs have minor allele frequencies of 0.24 or
greater in both EAs and AAs. This excess of high-frequency polymorphisms suggests that
balancing selection is occurring in this region.46 The most robust evidence for association in
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the collective data sets in this study was obtained with rs9387522, which is located in the 3′
UTR. The 3′ UTR is the major site of gene regulation by microRNA binding.47 Polymorphic
target sites for microRNA binding in the 3′ UTRs of SLITRK1, FGF20, and HTR1B have been
identified as leading to increased risk of Tourette syndrome,48 Parkinson disease,49 and
aggressive human behaviors,50 respectively. The possibility that MANEA 3′ UTR SNPs,
including rs987522, may influence risk of CD or CIP could be investigated by microRNA
studies in brains of rodents exposed to cocaine or constructs transfected into cell lines to
demonstrate effects on gene expression.
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We acknowledge several limitations to our study. First, our discovery sample, which was
ascertained through sibling pairs concordant for CD or opioid dependence, is probably enriched
for genetic factors for CD and CIP compared with subjects exposed to cocaine in the general
population. To overcome this issue and the problem that association findings in discovery
samples tend to overestimate the effect size of the genetic risk factor,51 we replicated our results
in independent EA and AA case-control samples. Although results with individual SNPs were
uneven across study samples, haplotype analysis showed significant association with the same
allele of 1 SNP (SNP 9, rs9387522) in both EA and both AA data sets. Second, genetic
association studies are vulnerable to false-positive results owing to population stratification
and to false-negative results owing to misclassification of subjects or power. Our use of familybased controls in the discovery phase and the assignment of nearly all subjects to genetically
matched groups based on analysis of many markers distributed across the genome lessened the
potential for stratification. Furthermore, all of the approximately 4000 subjects included in this
study were evaluated with a standardized instrument using a rigorous quality-control procedure
that reliably diagnoses substance dependence and other psychiatric disorders.21,26 In any event,
it is possible that some subjects were misclassified as controls because they were not
sufficiently exposed to cocaine to become dependent on the drug. This, however, would bias
the results toward the null hypothesis. Because our replication samples had sufficient power
to detect allele frequency differences of 7% to 10% for CIP and 8% to 15% for CD in either
population, lack of significant findings with individual SNPs in the EA sample could be
attributed to an inadequate sample size. However, significant haplotypic associations in this
population suggest that genetic background rather than sample size was the limiting factor.
Third, only one of the results from analyses of individual SNPs in the replication samples would
be considered significant after adjustment for multiple comparisons using a conservative
Bonferroni correction (threshold, P=.004 in EAs and P=.006 in AAs without taking intermarker
correlations into account). An alternative approach to evaluating the impact of multiple testing
on our results is measuring the rate of false discovery. Because the expected number of findings
for a trait that surpass a nominal significance level of P=.05 in the AA sample would be less
than 1 (0.05 × 9 informative SNPs × 0.5), assuming a 1-tailed test (and there were at least 3
significantly associated SNPs for each trait, taking into account the high correlation among
SNPs 5 through 9 in AAs [Figure]), it is unlikely that our findings for CD and CIP in the AA
replication sample are spurious. The significant global tests of association of MANEA
haplotypes with CD and CIP in the EA replication sample take into account the comparisons
of multiple haplo-types. In summary, our study shows that MANEA gene variants are strongly
associated with CD and CIP in both EA and AA populations. This finding, which was
discovered initially through a low-density genome scan, suggests that drug dependence and
associated behaviors may involve biological pathways not typically associated with brain
metabolism and opens a new pathway to understanding these highly prevalent disorders and
their psychopathologic manifestations.
Acknowledgments
Funding/Support: This work was supported by grants R01 DA12690, R01 DA12849, K24 DA15105, K24
DA022288, R01 AA11330, K24 AA13736, K05 AA017435, and M01 RR06192 from the National Institutes of Health.
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Some genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through
a contract from the National Institutes of Health to The Johns Hopkins University (N01-HG65403).
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Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
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Figure.
Locations and linkage disequilibrium map structure of single-nucleotide polymorphisms in the
MANEA gene region. Measures of linkage disequilibrium among all possible pairs of singlenucleotide polymorphisms (identified by marker number) are shown (white represents very
low D′ and dark red represents very high D′) and are numerically denoted by the r2 values
within each square. The MANEA gene structure, including intergenic regions (white), introns
(green), and exons (pink), is shown starting from the 5′ upstream region on the left. kb indicates
kilobases.
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
Farrer et al.
Page 12
Table 1
Characteristics of Subjects in a Genetic Study of Cocaine Dependence (CD) and Cocaine-Induced Paranoia (CIP)
No. of Subjects
NIH-PA Author Manuscript
Family Data Set
Characteristic
Total families
European American
Case-Control Data Set
African American
313
319
Total subjects (parents)
685 (38)
786 (26)
Additional genotyped subjects
(parents)
European American
African American
876
1045
75 (50)
66 (46)
Female sex, %
47.0
57.5
41.8
48.9
Subjects with CIP
403
443
309
430
Subjects with CD, without CIP
176
251
136
199
Subjects without CIP or CD,
controls
106
92
431
416
36.6 (8.7)
40.4 (6.3)
38.8 (8.9)
41.2 (7.5)
Age of subjects with CIP, mean
(SD), y
Age of subjects with CD,
without CIP, mean (SD), y
37.4 (8.3)
40.6 (6.2)
38.3 (9.8)
42.7 (7.4)
Age of controls, mean (SD), y
43.5 (15.3)
43.7 (12.2)
38.1 (14.6)
35.8 (12.8)
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
NIH-PA Author Manuscript
C/T
rs9387605
rs4388292
9
10
11
96 189 788
96 170 200
19 588
8544
348
11 907
4781
2724
11 420
2415
14 024
7195
Downstream of 3′ UTR
Downstream of 3′ UTR
3′ UTR
3′ UTR
Intron
Intron
Intron
Promoter
Promoter
Upstream of 5′ UTR
Upstream of 5′ UTR
Abbreviations: bp, base pairs; dbSNP, National Center for Biotechnology Information SNP database; SNP, single nucleotide polymorphism; UTR, untranslated region.
G/T
A/G
96 161 656
96 161 308
96 149 401
96 144 620
96 141 896
96 130 476
96 128 061
96 114 037
96 106 842
Included in Illumina SNP linkage panel.
a
C/T
rs9387522
8
A/C
G/T
A/G
rs1133503a
5
A/T
A/T
rs7757276
rs9374586
4
7
rs6937479
3
C/T
C/T
rs9400893
rs9320497
2
6
rs9400554
rs10782175
1
Marker No. dbSNP rs No. Alleles Map Location, bp Distance From Previous Marker, bp
SNP Type
NIH-PA Author Manuscript
Table 2
NIH-PA Author Manuscript
SNP Characteristics
Farrer et al.
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Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
NIH-PA Author Manuscript
G
C
C
A
T
rs7757276
rs1133503
rs9387522
rs9387605
rs4388292
c
T allele.
Significant result.
Informative families.
b
a
A
rs9400893
0.200
0.445
0.437
0.439
0.130
0.440
45
70
71
80
31
74
76
77
0.482c
0.385
70
59
82
Families, a No.
0.441
0.344
0.442
MAF
G
.03b
.45
A
.003b
0.283
0.377
0.378
0.373
T
.007b
0.378
0.128
G
0.324
0.398
.46
C
.01b
T
.07
.02b
0.359
.02b
0.467
MAF
0.160
T
Risk Allele
.64
.16
p Value
European American Families
54
62
64
68
39
63
59
63
58
40
67
Families,a No.
.77
.007b
.001b
G
A
T
T
.002b
G
.01b
C
.002b
T
<.001b
T
T
Risk Allele
<.001b
.003b
.28
.02b
P Value
African American Families
Abbreviations: CIP, cocaine-induced paranoia; MAF, minor allele frequency; SNP, single-nucleotide polymorphism.
T
rs9374586
A
rs9320497
A
T
rs6937479
T
rs10782175
Minor Allele
rs9400554
SNP
NIH-PA Author Manuscript
Table 3
0.237
0.415
0.411
0.410
0.129
0.412
0.358
0.465
0.405
0.264
0.452
MAF
99 .79
132 <.001b
135 <.001b
148 <.001b
70 .02b
137 <.001b
135 <.001b
140 <.001b
128 <.001b
99 .3
149 .009b
Families,a No. P Value
All Families
NIH-PA Author Manuscript
Association of MANEA SHPs With CIP in Discovery Samples
G
A
T
T
G
C
T
T
T
Risk Allele
Farrer et al.
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NIH-PA Author Manuscript
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
T
rs4388292
0.308
0.371
0.345
0.362
0.087
0.354
0.291
0.408
0.344
0.154
0.460
0.191
0.396
0.384
0.384
0.086
0.386
0.324
0.495
0.393
0.348
0.471
CIP Cases
0.289
0.325
0.319
0.330
0.076
0.329
0.276
0.365
0.322
0.145
0.500
0.170
0.412
0.393
0.392
0.094
0.398
0.310
0.417
0.401
0.401
0.100
0.404
0.320
0.429
0.389
0.156
0.458
0.141
0.421
0.410
0.416
0.097
0.416
0.354
0.498
0.496a
0.353
0.418
0.341
0.480
Controls
0.410
0.329
0.459
CD Cases
MAF
Allele
.01b
1.44 (1.09-1.92)b
1.01 (0.82-1.25)
1.21 (0.99-1.49)
1.27 (1.03-1.56)
1.18 (0.96-1.44)
1.16 (0.83-1.61)
1.24 (1.01-1.51)
1.14 (0.93-1.41)
ND
1.22 (0.99-1.49)
1.01 (0.78-1.32)
ND
1.24 (0.94-1.62)
1.48 (1.15-1.92)b
.02b
.02b
.92
1.10 (0.85-1.45)
1.43 (1.10-1.85)b
.007b
.11
.88
1.36 (1.06-1.76)b
.05
1.35 (0.87-2.09)
.02b
1.38 (1.07-1.78)b
.63
.02b
.37
.093
.04b
ND
1.35 (1.04-1.73)b
ND
1.09 (0.78-1.52)
.046b
ND
1.25 (0.86-1.83)
1.04 (0.78-1.38)
1.07 (0.81-1.43)
1.10 (0.83-1.47)
1.03 (0.65-1.65)
1.08 (0.81-1.43)
1.01 (0.75-1.35)
1.03 (0.78-1.35)
1.04 (0.78-1.37)
1.05 (0.78-1.42)
1.09 (0.83-1.44)
OR (95% CI)
.46
.003b
.007b
.02b
.18
.01b
.12
ND
.02b
.62
ND
.24
.79
.63
.48
.89
.60
.96
.86
.80
.73
.54
Allele
G
G
.046b
A
T
G
G
T
T
T
G
A
C
C
G
A
T
A
A
C
T
Risk Allele
.02b
.04b
.07
.39
.05
.32
ND
.07
.24
ND
.47
.97
.90
.79
.96
.88
.96
.27
.94
.26
.32
Genotype
P Value
CD vs Control
.05
ND
.04b
.58
.52
.35
.61
.42
.42
.70
.58
.37
.8
Genotype
.22
ND
.06
.92
ND
African American
.35
.33
.22
.46
.26
.24
.92
.34
.76
.73
1.11 (0.89-1.38)
1.11 (0.90-1.39)
1.14 (0.92-1.42)
1.15 (0.80-1.65)
1.13 (0.91-1.40)
1.14 (0.92-1.43)
1.01 (0.82-1.25)
1.10 (0.90-1.37)
1.03 (0.83-1.29)
1.04 (0.84-1.28)
European American
OR (95% CI)
P Value
CIP vs Control
Abbreviations: CD, cocaine dependence; CI, confidence interval; CIP, cocaine-induced paranoia; MAF, minor allele frequency; ND, test not done because controls were not in Hardy-Weinberg
equilibrium; OR, odds ratio; SNP, single nucleotide polymorphism.
C
A
rs9387605
C
rs1133503
rs9387522
G
A
rs6937479
rs7757276
A
rs9320497
T
T
rs10782175
A
T
rs9400554
rs9400893
T
rs4388292
rs9374586
C
A
C
rs1133503
rs9387605
G
rs7757276
rs9387522
T
A
rs9400893
A
rs6937479
rs9374586
T
A
rs9320497
T
Minor Allele
rs10782175
rs9400554
SNP
NIH-PA Author Manuscript
Table 4
NIH-PA Author Manuscript
Association of MANEA SNPs With CIP and CD in Replication Samples
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NIH-PA Author Manuscript
Significant result.
b
a
NIH-PA Author Manuscript
T allele.
NIH-PA Author Manuscript
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
NIH-PA Author Manuscript
C
A
C
A
C
T
T
C
C
T
0.006
0.12
0.4
0.47
0
0.12
0.4
0.474
Haplotypic Frequency
Significant result.
c
In European Americans: global, P=.003; in African Americans: global, P=.06.
b
-0.64
2.86
2.25
-0.81
-1.08
2.25
-1
P Value
0.31
0.22
0.06
.02b
.004b
0.41
.42
.28
Cocaine Dependencec
0.23
0.06
0.31
.02b
0.4
Haplotypic Frequency
.32
.52
Cocaine-Induced Paranoiaa
Z Score
European Americans
In European Americans: global, P=.04; in African Americans: global, P=.14.
C
A
C
A
T
C
rs9387522
Allele by SNP
rs9400554
a
NIH-PA Author Manuscript
Table 5
-1.67
0.74
-1.92
1 99
-1.7
1.55
-1.32
0.7
Z Score
African Americans
.09
.46
.06
.046b
.09
.12
.19
.48
P Value
NIH-PA Author Manuscript
Haplotype Association of MANEA With Cocaine-Induced Paranoia in the Replication Samples
Farrer et al.
Page 17
Arch Gen Psychiatry. Author manuscript; available in PMC 2009 October 6.
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