Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals.

BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (ß = 0.12, P = 2.7 × 10-4) and with the Han/Eskin random effects method (P = 1.4 × 10-7) but not with traditional random effects (ß = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (ß = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10-8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTOConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder.

BACKGROUND: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD. METHODS: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity. RESULTS: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P < 0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ(2) = 27.68; P < 0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ(2) = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results. CONCLUSIONS: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity.

Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders.

Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: a genome-wide association and polygenic scoring study.

Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis.

Dissecting the genetic heterogeneity of depression through age at onset.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.

Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder.

It has been suggested that alteration in the muscarinic-cholinergic system is involved in modulation of mood. Three studies have reported linkage on chromosome 7 with major depressive disorder (MDD) in or close to a region containing the muscarinic receptor CHRM2 gene. A haplotype of SNPs located in CHRM2 (rs1824024-rs2061174-rs324650) has been significantly associated with MDD in a previous study. We report the first study investigating this gene in a large, adequately powered, clinical depression case-control sample (n = 1420 cases, 1624 controls). Our data fail to support association with the CHRM2 polymorphisms previously implicated in the genetic aetiology of depression. It is possible our failure to replicate may be a consequence of differences in definition of the MDD phenotype and/or ethnic differences.

A genome-wide association study of social and non-social autistic-like traits in the general population using pooled DNA, 500 K SNP microarrays and both community and diagnosed autism replication samples.

Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in approximately 430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low-scoring boys from a general population sample (N = approximately 400/group). In Stage 2, 22 and 20 SNPs in the social and non-social studies, respectively, were tested for QTL association by individually genotyping an independent community sample of 1,400 boys. One SNP (rs11894053) was nominally associated (P < .05, uncorrected for multiple testing) with social autistic-like traits. When the sample was increased by adding females, 2 additional SNPs were nominally significant (P < .05). These 3 SNPs, however, showed no significant association in transmission disequilibrium analyses of diagnosed ASD families.

Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism.

Children's intellectual development is influenced by both genetic inheritance and environmental experiences. Breastfeeding is one of the earliest such postnatal experiences. Breastfed children attain higher IQ scores than children not fed breast milk, presumably because of the fatty acids uniquely available in breast milk. Here we show that the association between breastfeeding and IQ is moderated by a genetic variant in FADS2, a gene involved in the genetic control of fatty acid pathways. We confirmed this gene-environment interaction in two birth cohorts, and we ruled out alternative explanations of the finding involving gene-exposure correlation, intrauterine growth, social class, and maternal cognitive ability, as well as maternal genotype effects on breastfeeding and breast milk. The finding shows that environmental exposures can be used to uncover novel candidate genes in complex phenotypes. It also shows that genes may work via the environment to shape the IQ, helping to close the nature versus nurture debate.

Brain monoamine oxidase A activity predicts trait aggression.

The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

Genetics of human aggressive behaviour.

A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual differences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual differentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major effect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These findings will have major significance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants affecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.

Genes within the serotonergic system are differentially expressed in human brain.

BACKGROUND: Serotonin is an important neurotransmitter with wide-ranging functions throughout the central nervous system. There is strong evidence to suggest that regulation of serotonergic gene expression might be related to genetic variability, and several studies have focused on understanding the functional effects of specific polymorphisms within these genes on expression levels. However, the combination of genotype together with gender and brain region could have an overall effect on gene expression. In this study, we report expression patterns of five serotonergic genes (TPH1, TPH2, 5-HT2A, 5-HT2C, 5-HTT) in seven different human post-mortem brain regions (superior frontal gyrus, superior temporal gyrus, striatum, cerebellum, hippocampus, midbrain and thalamus) using TaqMan real-time quantitative PCR. In addition, the effect of genotype and gender on their expression levels was determined. RESULTS: The data revealed that mRNA from the five genes investigated was detected in all brain regions and showed an overall significant difference in expression levels. Furthermore, the expression of 5-HT2C, 5-HT2A and TPH2 was found to be significantly different between the various brain regions. However, neither gender nor genotype showed significant effects on the expression levels of any of the genes assayed. Interestingly, TPH1 and TPH2 were expressed in all brain regions similarly except for within the striatum and cerebellum, where TPH1 was expressed at a significantly higher level than TPH2. CONCLUSION: The effect of brain region has a greater influence on serotonergic gene expression than either genotype or gender. These data add to the growing body of evidence that effects of functional polymorphisms on gene expression in vitro are not observed ex vivo, and provide information that will aid in the design of expression studies of the serotonergic gene system within human post-mortem brain.

Neural mechanisms of anger regulation as a function of genetic risk for violence.

Genetic risk may predispose individuals to compromised anger regulation, potentially through modulation of brain responses to emotionally evocative stimuli. Emphatically expressed, the emotional word No can prohibit behavior through conditioning. In a recent functional magnetic resonance imaging study, the authors showed that healthy males attribute negative valence to No while showing a lateral orbitofrontal response that correlated with their self-reported anger control. Here, the authors examined the influence of the monoamine oxidase A (MAOA) gene (low vs. high transcription variants) on brain response to No and in relationship to trait anger reactivity and control. The orbitofrontal response did not differ as a function of the genotype. Instead, carriers of the low-MAOA genotype had reduced left middle frontal gyrus activation to No compared with the high variant. Furthermore, only for carriers of the up low-MAOA genotype, left amygdala and posterior thalamic activation to No increased with anger reactivity. Thus, vulnerability to aggression in carriers of the low-MAOA genotype is supported by decreased middle frontal response to No and the unique amygdala/thalamus association pattern in this group with anger reactivity but not anger control.

Assessing individual differences in genome-wide gene expression in human whole blood: reliability over four hours and stability over 10 months.

Studying the causes and correlates of natural variation in gene expression in healthy populations assumes that individual differences in gene expression can be reliably and stably assessed across time. However, this is yet to be established. We examined 4-hour test-retest reliability and 10 month test-retest stability of individual differences in gene expression in ten 12-year-old children. Blood was collected on four occasions: 10 a.m. and 2 p.m. on Day 1 and 10 months later at 10 a.m. and 2 p.m. Total RNA was hybridized to Affymetrix-U133 plus 2.0 arrays. For each probeset, the correlation across individuals between 10 a.m. and 2 p.m. on Day 1 estimates test-retest reliability. We identified 3,414 variable and abundantly expressed probesets whose 4-hour test-retest reliability exceeded .70, a conventionally accepted level of reliability, which we had 80% power to detect. Of the 3,414 reliable probesets, 1,752 were also significantly reliable 10 months later. We assessed the long-term stability of individual differences in gene expression by correlating the average expression level for each probe-set across the two 4-hour assessments on Day 1 with the average level of each probe-set across the two 4-hour assessments 10 months later. 1,291 (73.7%) of the 1,752 probe-sets that reliably detected individual differences across 4 hours on two occasions, 10 months apart, also stably detected individual differences across 10 months. Heritability, as estimated from the MZ twin intraclass correlations, is twice as high for the 1,752 reliable probesets versus all present probesets on the array (0.68 vs 0.34), and is even higher (0.76) for the 1,291 reliable probesets that are also stable across 10 months. The 1,291 probesets that reliably detect individual differences from a single peripheral blood collection and stably detect individual differences over 10 months are promising targets for research on the causes (e.g., eQTLs) and correlates (e.g., psychopathology) of individual differences in gene expression.

Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.

The MAO-A genotype does not modulate resting brain metabolism in adults.

Variation in the monoamine-oxidase-A (MAO-A) gene has been associated with volumetric changes in corticolimbic regions with differences in their response to relevant emotional tasks. Here we show no changes in baseline regional brain metabolism as a function of genotype indicating that, unchallenged, corticolimbic activity is not modulated by the MAO-A genotype.

Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins.

Monozygotic (MZ) twins may be subject to epigenetic modifications that could result in different patterns of gene expression. Several lines of evidence suggest that epigenetic factors may underlie mental disorders such as bipolar disorder (BD) and schizophrenia (SZ). One important epigenetic modification, of relevance to female MZ twins, is X-chromosome inactivation. Some MZ female twin pairs are discordant for monogenic X linked disorders because of differential X inactivation. We postulated that similar mechanisms may also occur in disorders with more complex inheritance including BD and SZ. Examination of X-chromosome inactivation patterns in DNA samples from blood and/or buccal swabs in a series of 63 female MZ twin pairs concordant or discordant for BD or SZ and healthy MZ controls suggests a potential contribution from X-linked loci to discordance within twin pairs for BD but is inconclusive for SZ. Discordant female bipolar twins showed greater differences in the methylation of the maternal and paternal X alleles than concordant twin pairs and suggest that differential skewing of X-chromosome inactivation may contribute to the discordance observed for bipolar disorder in female MZ twin pairs and the potential involvement of X-linked loci in the disorder.

Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP).

A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10-9) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10-5). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies.

Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects.

BACKGROUND: A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. METHODS: Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism. RESULTS: There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. CONCLUSIONS: The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.

A central resource for accurate allele frequency estimation from pooled DNA genotyped on DNA microarrays.

Analysing pooled DNA on microarrays is an efficient way to genotype hundreds of individuals for thousands of markers for genome-wide association. Although direct comparison of case and control fluorescence scores is possible, correction for differential hybridization of alleles is important, particularly for rare single nucleotide polymorphisms. Such correction relies on heterozygous fluorescence scores and requires the genotyping of hundreds of individuals to obtain sufficient estimates of the correction factor, completely negating any benefit gained by pooling samples. We explore the effect of differential hybridization on test statistics and provide a solution to this problem in the form of a central resource for the accumulation of heterozygous fluorescence scores, allowing accurate allele frequency estimation at no extra cost.