Functional Connectivity Analyses in Imaging Genetics: Considerations on Methods and Data Interpretation

Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders (“imaging genetics”). A data analysis approach that is widely applied is “functional connectivity”. In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called “seed point”) and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

© 2014, The Author(s).Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder

Vitamin B12 status in patients of Turkish and Dutch descent with depression: A comparative cross-sectional study

Background: Studies have shown a clear relationship between depressive disorders and vitamin B12 deficiency. Gastroenteritis and Helicobacter pylori infections can cause vitamin B12 deficiency. Helicobacter pylori infections are not uncommon among people of Turkish descent in The Netherlands. Aim: To examine the frequency of vitamin B12 deficiency in depressive patients of Turkish descent and compare it to the frequency of vitamin B12 deficiency in depressive patients of Dutch descent. Methods: The present study is a comparative cross-sectional study of 47 patients of Turkish descent and 28 of Dutch descent. The depressive disorder diagnosis and differential diagnosis were made using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition text revision (SCID). The severity of the depressive symptoms was determined using the Beck Depression Inventory (BDI) and the 21-item Hamilton Depression Rating Scale (HAM-D-21). Serum baseline vitamin B6 and B12, folic acid and total serum homocysteine (tHcy) levels were measured. Results: The average ages of the patients of Turkish and Dutch descent were 40.57 and 44.75 years, respectively. There were no demonstrable differences between the serum vitamin B6, folic acid and tHcy levels in the two groups. The serum vitamin B12 levels were however clearly lower in the patients of Turkish descent than in those of Dutch descent. Vitamin B12 deficiency was however observed in 14 patients of Turkish descent and 1 of Dutch descent. This difference was significant. On the BDI, the patients of Turkish descent scored significantly higher than those of Dutch descent. Patients with vitamin B12 deficiency and those with hyperhomocysteinaemia had a significantly higher BDI score than patients with normal vitamin B12 and homocysteine levels. No relationship was observed with vitamin B12 and tHcy. Conclusion: Vitamin B12 deficiency occurs more frequently in depressive patients of Turkish than of Dutch descent. This is why it is advisable to test the vitamin B12 serum level in depressive patients of Turkish descent

The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

Contains fulltext : 98431.pdf (publisher's version ) (Open Access)RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects of stressful events on BDNF levels may in part be conditional upon a common variant on the BDNF gene (Val(66)Met; RS6265), with the Met allele being associated with a decrease in activity-dependent secretion of BDNF compared to the Val allele. METHODS: We investigated cross-sectionally in 1,435 individuals with lifetime MDD the impact of childhood abuse (CA) and recent life events on serum BDNF levels and assessed whether the impact of these events was moderated by the BDNF Val(66)Met polymorphism. RESULTS: Overall, BDNF Met carriers had reduced serum BDNF levels when exposed to CA in a dose-dependent way. Moreover, exposure to recent life events was also associated with decreases in BDNF levels, but this was independent of BDNF Val(66)Met. Moreover, when not exposed to CA, Met carriers had higher BDNF levels than the Val/Val individuals, who did not show decreases in BDNF associated with CA. Finally, these findings were only apparent in the MDD group without comorbid anxiety. CONCLUSIONS: These gene-environment interactions on serum BDNF levels suggest that Met carriers are particularly sensitive to (early) stressful life events, which extends previous findings on the moderating role of the BDNF Val(66)Met polymorphism in the face of stressful life events

Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2

Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent findings with respect to the functional analysis of TPH2

Altered Gene Synchrony Suggests a Combined Hormone-Mediated Dysregulated State in Major Depression

Coordinated gene transcript levels across tissues (denoted “gene synchrony”) reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001). Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects) and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here “depression”) (n = 14; MDD/Permutated data, p<0.000001), significantly affecting between 100 and 250 individual genes (10–30% false discovery rate). Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression

Prioritization and Evaluation of Depression Candidate Genes by Combining Multidimensional Data Resources

Large scale and individual genetic studies have suggested numerous susceptible genes for depression in the past decade without conclusive results. There is a strong need to review and integrate multi-dimensional data for follow up validation. The present study aimed to apply prioritization procedures to build-up an evidence-based candidate genes dataset for depression.Depression candidate genes were collected in human and animal studies across various data resources. Each gene was scored according to its magnitude of evidence related to depression and was multiplied by a source-specific weight to form a combined score measure. All genes were evaluated through a prioritization system to obtain an optimal weight matrix to rank their relative importance with depression using the combined scores. The resulting candidate gene list for depression (DEPgenes) was further evaluated by a genome-wide association (GWA) dataset and microarray gene expression in human tissues.A total of 5,055 candidate genes (4,850 genes from human and 387 genes from animal studies with 182 being overlapped) were included from seven data sources. Through the prioritization procedures, we identified 169 DEPgenes, which exhibited high chance to be associated with depression in GWA dataset (Wilcoxon rank-sum test, p = 0.00005). Additionally, the DEPgenes had a higher percentage to express in human brain or nerve related tissues than non-DEPgenes, supporting the neurotransmitter and neuroplasticity theories in depression.With comprehensive data collection and curation and an application of integrative approach, we successfully generated DEPgenes through an effective gene prioritization system. The prioritized DEPgenes are promising for future biological experiments or replication efforts to discover the underlying molecular mechanisms for depression

A Network of Genes, Genetic Disorders, and Brain Areas

The network-based approach has been used to describe the relationship among genes and various phenotypes, producing a network describing complex biological relationships. Such networks can be constructed by aggregating previously reported associations in the literature from various databases. In this work, we applied the network-based approach to investigate how different brain areas are associated to genetic disorders and genes. In particular, a tripartite network with genes, genetic diseases, and brain areas was constructed based on the associations among them reported in the literature through text mining. In the resulting network, a disproportionately large number of gene-disease and disease-brain associations were attributed to a small subset of genes, diseases, and brain areas. Furthermore, a small number of brain areas were found to be associated with a large number of the same genes and diseases. These core brain regions encompassed the areas identified by the previous genome-wide association studies, and suggest potential areas of focus in the future imaging genetics research. The approach outlined in this work demonstrates the utility of the network-based approach in studying genetic effects on the brain

A functional alternative splicing mutation in human tryptophan hydroxylase-2

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter- individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y ( NPY) is anxiolytic(1,2) and its release is induced by stress(3). NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories(4-6). Here we show that haplotype- driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype- driven NPY expression predicted higher emotion- induced activation of the amygdala, as well as diminished resiliency as assessed by pain/ stress- induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism ( SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter- individual variation in resiliency to stress, a risk factor for many diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62768/1/nature06858.pd