It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3' and 5' untranslated regions (P = 1.84×10(-5) and 4.7×10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9×10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10(-10)). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated.

/pdf/unraveling-the-regulatory-mechanisms-underlying-tissue-33flcuftpe.pdf

Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression

Christodoulou C, Douzenis A, Papadopoulos FC, Papadopoulou A, Bouras G, Gournellis R, Lykouras L. Suicide and seasonality.

Objective:  Seasonal variation of deaths by suicide offers an important pathway in the study of possible suicide determinants of suicide and consequently suicide prevention.

Method:  We conducted a review of the literature on suicide seasonality, assessing articles published between 1979 and 2009.

Results:  The majority of the studies confirm a peak in spring, mainly for men, older individuals, and violent methods of suicide. A secondary peak during autumn is observed. There is no common seasonality pattern for suicide methods. However, there are also certain studies that did not confirm seasonal variation. Inconsistent results with reduced, unchanged, and even increased suicide seasonality have been reported. Aspects on the association between seasonality and suicides are discussed. Except sex, age, and method of suicide, other parameters were taken into account to find more specific characteristics of seasonality in suicides as well. The influence of clinical, bioclimatic, sociodemographic as well as biological factors seems to affect the seasonal variation.

Conclusion:  Studies from both the Northern and the Southern hemisphere report a seasonal pattern for suicides. These studies are not only an important source of epidemiological data for suicides but also represent a global effort to uncover hidden parameters of this self-destructive behaviour.

Suicide and seasonality

Recent meta-analyses have stimulated an active debate on whether the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is associated with an elevated vulnerability to psychiatric diseases upon exposure to environmental adversity. As a potential mechanism explaining genotype-dependent differences in stress sensitivity, altered stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis has been investigated in several experimental studies, with most of these studies comprising small samples. We evaluated the association of 5-HTTLPR genotype and cortisol reactivity to acute psychosocial stress by applying a meta-analytical technique based on eleven relevant data sets (total N=1686), which were identified through a systematic literature search up to October 2011. This meta-analysis indicates a small (d=0.27), but significant association between 5-HTTLPR genotype and HPA-axis reactivity to acute psychosocial stress with homozygous carriers of the S allele displaying increased cortisol reactivity compared with individuals with the S/L and L/L genotype. The latter association was not further moderated by participants' age, sex or the type of stressor. Formal testing revealed no evidence for a substantial selection or publication bias. Our meta-analytical results are consistent with a wide variety of experimental studies indicating a significant association between 5-HTTLPR genotype and intermediate phenotypes related to stress sensitivity. Future studies are needed to clarify the consistency of this effect and to further explore whether altered HPA-axis stress reactivity reflects a potential biological mechanism conveying an elevated risk for the development of stress-related disorders in S allele carriers.

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis

Vitamin D receptors and vitamin D metabolizing enzymes are present in the central nervous system. Calcitriol (the active vitamin D hormone) affects numerous neurotransmitters and neurotrophic factors, relevant for mental disorders. In the case of depressive disorders, considerable evidence supports a role of suboptimal vitamin D levels. However, the data are not conclusive and further studies are necessary. Especially, the relative importance of the pineal-melatonin system versus the vitamin D-endocrine system for the pathogenesis of seasonal affective disorders is presently unresolved. Two diagnoses, schizophrenia and autism, have been hypothetically linked to developmental (prenatal) vitamin D deficiency, however, also in adult patients, low levels have been reported, supporting the notion that vitamin D deficiency may not only be a predisposing developmental factor but also relate to the adult patients' psychiatric state. Two cases are described, whose psychiatric improvement coincided with effective treatment of vitamin D deficiency.

Vitamin D, light and mental health

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(4) receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

/pdf/5-ht-radioligands-for-human-brain-imaging-with-pet-and-spect-2dwv9akol0.pdf

5-HT radioligands for human brain imaging with PET and SPECT.

Seasonal Changes in Brain Serotonin Transporter Binding in Short Serotonin Transporter Linked Polymorphic Region-Allele Carriers but Not in Long-Allele Homozygotes

A non-synonymous polymorphism in galactose mutarotase ( GALM ) is associated with serotonin transporter binding potential in the human thalamus: results of a genome-wide association study

/pdf/a-non-synonymous-polymorphism-in-galactose-mutarotase-galm-18fqoha8sc.pdf

A non-synonymous polymorphism in galactose mutarotase (GALM) is associated with serotonin transporter binding potential in the human thalamus: results of a genome-wide association study.

Tine E. Arentzen

Papers

Seasonal Changes in Brain Serotonin Transporter Binding in Short Serotonin Transporter Linked Polymorphic Region-Allele Carriers but Not in Long-Allele Homozygotes

A non-synonymous polymorphism in galactose mutarotase (GALM) is associated with serotonin transporter binding potential in the human thalamus: results of a genome-wide association study.