Sex-specific influence of DRD2 on ADHD-type temperament in a large population-based birth cohort.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a significant public-health impact. Previously, we described a candidate gene study in a population-based birth cohort that demonstrated an association with ADHD-affected males and the dopamine receptor D2 (DRD2). The current study evaluates potential associations of dopamine receptor genes and Cloninger temperament traits within this same sample. Participants with stringent lifetime ADHD diagnoses were ascertained systematically from the genetically isolated Northern Finland 1986 Birth Cohort (n=9432), resulting in 178 cases and 157 controls. Markers in all known dopamine receptor genes were genotyped. We report an association of DRD2 with low Persistence in females (rs1079727 P=0.02, rs1124491 P=0.02, rs1800497 P=0.03). The associated DRD2 minor allelic haplotype (CAA, P=0.03) is the same haplotype we previously associated with ADHD in males in this birth cohort. The current study further supports previous results on the role of DRD2 in individuals with ADHD. Investigations suggest that DRD2 may have an impact on both males and females, but the particular outcome appears sex-specific, manifesting as ADHD in males and low Persistence in females. Furthermore, these findings suggest that the putative role of low Persistence as an endophenotype for ADHD deserves further investigation.

Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort.

Objectives Depression is a worldwide leading cause of morbidity and disability. Genetic studies have recently begun to elucidate its molecular aetiology. The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 (12 058 live births). Design The authors ascertained and subdivided the study sample (n=5225) based on measures of early development and of social environment, and examined candidate genes of monoamine neurotransmission, many of which have shown prior evidence of a gene-environment interaction for affective disorders, namely SLC6A4, TPH2, COMT, MAOA and the dopamine receptor genes DRD1-DRD5. Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness. However, when measures of early development and of social environment were considered, some evidence of interaction was observed. Allelic variants of COMT interacted with high early developmental risk (p=0.005 for rs2239393 and p=0.02 for rs4680) so that the association with depression was detected only in individuals at high developmental risk group (p=0.0046 and ß=0.056 for rs5993883-rs2239393-rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and ß=0.083 for the haplotype CGG). Rs4274224 from DRD2 interacted with gender (p=0.017) showing a significant association with depressiveness in males (p=0.0006 and ß=0.0023; p=0.00005 and ß=0.069 for rs4648318-rs4274224 haplotype GG). The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex, but not direct major effects of monoaminergic genes in this unselected population.

Impact of the dopamine receptor gene family on temperament traits in a population-based birth cohort.

Although the genetic determinants of personality have been intensively investigated especially since Cloninger proposed his psychobiological model of temperament and character, findings to date remain inconclusive and very few studies have addressed the topic in large population cohorts. In the current study we investigated one gene family in its entirety by addressing the role of all known dopamine receptor genes, DRD1-DRD5, on Cloninger's temperament traits in a Finnish population-based birth cohort. The study sample (n = 1,434) was ascertained from the Northern Finland Birth Cohort 1966 with over 5,000 study individuals tested at the age of 31 years. We utilized the genetic homogeneity and genealogical structure of this population to uncover putative effects of these genes on temperament traits at the population level. Our strategy utilizing a large birth cohort and its well established genealogical structure represents an optimal design for studying normally distributed traits. We also wished to provide a comprehensive view to one biologically relevant gene family instead of testing single candidate genes. We report evidence of association of several SNPs at the 5' end of dopamine receptor D2 (DRD2) with Novelty seeking (low) and Harm avoidance (high), and at the 3' end of DRD2 with Persistence. The strongest evidence of association emerged from females. Our study supports the involvement of the dopamine pathway in temperament traits, in particular underlining the role of DRD2 in Novelty seeking, Harm avoidance and Persistence.

ADHD candidate gene study in a population-based birth cohort: association with DBH and DRD2.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset disorder with a significant impact on public health. Although a genetic contribution to risk is evident, predisposing genetic determinants remain largely unknown despite extensive research. So far, the most promising candidate genes have been those involved in dopamine and serotonin pathways. This study tests a series of allelic variants within such candidate genes to determine their potential influence on ADHD susceptibility. METHOD: We used a population sample ascertained from a birth cohort of a subpopulation of Finland, characterized by founder effect and isolation, thus minimizing genetic heterogeneity. The subjects were systematically ascertained using DSM-IV diagnostic criteria for ADHD from the Northern Finland Birth Cohort 1986 of more than 9,000 individuals, resulting in the study sample of 188 ADHD cases and 166 controls. We genotyped markers in 13 candidate genes, including critical components of dopamine and serotonin pathways. RESULTS: We report evidence for association of ADHD with allelic variants of the dopamine beta-hydroxylase (DBH) and dopamine receptor D2 (DRD2) genes. CONCLUSIONS: Our study supports the involvement of the dopamine pathway in the etiology of ADHD; specifically the genes DBH and DRD2 deserve more attention in further studies.

Research advances in the use of tetrapyrrolic photosensitizers for photodynamic therapy.

Photodynamic therapy (PDT) is a promising new treatment modality for several diseases, most notably cancer. In PDT, light, O2, and a photosensitizing drug are combined to produce a selective therapeutic effect. Lately, there has been active research on new photosensitizer candidates, because the most commonly used porphyrin photosensitizers are far from ideal with respect to PDT. Finding a suitable photosensitizer is crucial in improving the efficacy of PDT. Recent synthetic activity has created such a great number of potential photosensitizers for PDT that it is difficult to decide which ones are suitable for which pathological conditions, such as various cancer species. To facilitate the choice of photosensitizer, this review presents a thorough survey of the photophysical and chemical properties of the developed tetrapyrrolic photosensitizers. Special attention is paid to the singlet-oxygen yield (PhiDelta) of each photosensitizer, because it is one of the most important photodynamic parameters in PDT. Also, in the survey, emphasis is placed on those photosensitizers that can easily be prepared by partial syntheses starting from the abundant natural precursors, protoheme and the chlorophylls. Such emphasis is justified by economical and environmental reasons. Several of the most promising photosensitizer candidates are chlorins or bacteriochlorins. Consequently, chlorophyll-related chlorins, whose PhiDelta have been determined, are discussed in detail as potential photosensitizers for PDT. Finally, PDT is briefly discussed as a treatment modality, including its clinical aspects, light sources, targeting of the photosensitizer, and opportunities.