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Genetic neuropathology of obsessive psychiatric syndromes.

Jaffe AE, Deep-Soboslay A, Tao R, Hauptman DT, Kaye WH, Arango V, Weinberger DR, Hyde TM, Kleinman JE - Transl Psychiatry (2014)

Bottom Line: Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings.Several risk-predisposing SNPs were significantly associated with gene expression among control subjects.However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA.

ABSTRACT
Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

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Top expression quantitative trait loci (eQTLs) of ED clinical risk variants associated with gene expression in nonpsychiatric controls (N=268). (a) The effect of SNP rs674386 on LUZP1 expression and (b) the effect of rs1503433 on CGGBP1 expression. Y axis is log2 expression relative to a reference pool, adjusted for surrogate variables, sex and race.
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fig1: Top expression quantitative trait loci (eQTLs) of ED clinical risk variants associated with gene expression in nonpsychiatric controls (N=268). (a) The effect of SNP rs674386 on LUZP1 expression and (b) the effect of rs1503433 on CGGBP1 expression. Y axis is log2 expression relative to a reference pool, adjusted for surrogate variables, sex and race.

Mentions: We first interrogated the potential functional relevance of the candidate ED risk SNPs by exploring their effect on gene expression in nonpsychiatric controls in the human prefrontal cortex. We performed an expression quantitative trait loci (eQTLs) analysis in postmortem brain tissue from 268 nonpsychiatric controls across the lifespan using 105 identified clinical risk SNPs for ED/OCD (see Materials and Methods) to understand how genetic variation at these loci are associated with nearby gene expression in the ‘normal' human brain. We first performed a local cis analysis—each SNP was associated with expression levels for all genes within one megabase upstream or downstream, and identified only two significant loci (Supplementary Table 3). The top cis signal involved four correlated SNPs annotated to the locus of HTR1D (rs7532266, rs674386, rs588387 and rs856510) at chr11:23521835-23551623, which was at least marginally significant in three independent studies.11,29,30 While this genetic locus contained HTR1D, the clinical risk variants were actually associated with the expression of LUZP1 (P=2.08 × 10−11, FDR=6.73 × 10−8), an adjacent gene 26 kb upstream that encodes a protein containing a leucine zipper motif (Figure 1a). Similarly, the other significant cis signal involved genetic variation in the HTR1F gene associating with the expression levels of the adjacent CGGBP1 gene (Figure 1b), a CGG triplet binding protein involved in fragile X syndrome and intellectual disability.31


Genetic neuropathology of obsessive psychiatric syndromes.

Jaffe AE, Deep-Soboslay A, Tao R, Hauptman DT, Kaye WH, Arango V, Weinberger DR, Hyde TM, Kleinman JE - Transl Psychiatry (2014)

Top expression quantitative trait loci (eQTLs) of ED clinical risk variants associated with gene expression in nonpsychiatric controls (N=268). (a) The effect of SNP rs674386 on LUZP1 expression and (b) the effect of rs1503433 on CGGBP1 expression. Y axis is log2 expression relative to a reference pool, adjusted for surrogate variables, sex and race.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4203002&req=5

fig1: Top expression quantitative trait loci (eQTLs) of ED clinical risk variants associated with gene expression in nonpsychiatric controls (N=268). (a) The effect of SNP rs674386 on LUZP1 expression and (b) the effect of rs1503433 on CGGBP1 expression. Y axis is log2 expression relative to a reference pool, adjusted for surrogate variables, sex and race.
Mentions: We first interrogated the potential functional relevance of the candidate ED risk SNPs by exploring their effect on gene expression in nonpsychiatric controls in the human prefrontal cortex. We performed an expression quantitative trait loci (eQTLs) analysis in postmortem brain tissue from 268 nonpsychiatric controls across the lifespan using 105 identified clinical risk SNPs for ED/OCD (see Materials and Methods) to understand how genetic variation at these loci are associated with nearby gene expression in the ‘normal' human brain. We first performed a local cis analysis—each SNP was associated with expression levels for all genes within one megabase upstream or downstream, and identified only two significant loci (Supplementary Table 3). The top cis signal involved four correlated SNPs annotated to the locus of HTR1D (rs7532266, rs674386, rs588387 and rs856510) at chr11:23521835-23551623, which was at least marginally significant in three independent studies.11,29,30 While this genetic locus contained HTR1D, the clinical risk variants were actually associated with the expression of LUZP1 (P=2.08 × 10−11, FDR=6.73 × 10−8), an adjacent gene 26 kb upstream that encodes a protein containing a leucine zipper motif (Figure 1a). Similarly, the other significant cis signal involved genetic variation in the HTR1F gene associating with the expression levels of the adjacent CGGBP1 gene (Figure 1b), a CGG triplet binding protein involved in fragile X syndrome and intellectual disability.31

Bottom Line: Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings.Several risk-predisposing SNPs were significantly associated with gene expression among control subjects.However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Sciences, Lieber Institute for Brain Development, Baltimore, MD, USA.

ABSTRACT
Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

Show MeSH
Related in: MedlinePlus