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In 1990, Blum and colleagues first reported an association between DRD2 and alcoholism. While there have been subsequent replications of this genetic association, there have also been numerous studies that failed to detect an association between DRD2 and alcohol dependence. We propose that one aspect contributing to this inconsistency is the variation in alcohol phenotype used across studies. Within the population-based Finnish twin sample, FinnTwin16, we previously performed multivariate twin analyses to extract latent genetic factors, which account for the variation across seven measures of alcohol consumption (frequency of drinking, frequency × quantity, frequency of heavy drinking, frequency of intoxication and maximum drinks in a 24-hour period) and problems (the Rutgers Alcohol Problem Index-RAPI and the Malmo-modified Michigan Alcohol Screen Test-MmMAST) in 3065 twins. In the present study, we examined the association between 31 DRD2/ANKK1 single-nucleotide polymorphisms (SNPs) and the genetic factor scores generated by twin analyses in a subset of FinnTwin16 (n = 602). We focus on two of the genetic factors: a general alcohol consumption and problems factor score, which represents shared genetic variance across alcohol measures, and a alcohol problems genetic factor score, which loads onto the two indices of problematic drinking (MAST and RAPI). After correction for multiple testing across SNPs and phenotypes, of the 31 SNPs genotyped across DRD2/ANKK1, one SNP (rs10891549) showed significant association with the general alcohol consumption and problems factor score (P = 0.004), and four SNPs (rs10891549, rs1554929, rs6275, rs6279), representing two independent signals after accounting for linkage disequilibrium, showed significant association with the alcohol problems genetic factor score (P = 0.005, P = 0.005, P = 0.003, P = 0.003). In this study, we provide additional positive evidence for the association between DRD2/ANKK1 and alcohol outcomes, including frequency of drinking and drinking problems. Additionally, post hoc analyses indicate stronger association signals using genetic factor scores than individual measures, which suggest that accounting for the genetic architecture of the alcohol measures reduces genetic heterogeneity in alcohol dependence outcomes in this sample and enhances the ability to detect association.

Background The aim of this study was to characterize at the population level how innate features of temperament relate to experience of depressive mood and anxiety, and whether these symptoms have separable temperamental backgrounds. Methods The study subjects were 4773 members of the population-based Northern Finland Birth Cohort 1966, a culturally and genetically homogeneous study sample. Temperament was measured at age 31 using the temperament items of the Temperament and Character Inventory and a separate Pessimism score. Depressive mood was assessed based on a previous diagnosis of depressive disorder or symptoms of depression according to the Hopkins Symptom Check List – 25. Anxiety was assessed analogously. Results High levels of Harm avoidance and Pessimism were related to both depressive mood (effect sizes; d = 0.84 and d = 1.25, respectively) and depressive disorder (d = 0.68 and d = 0.68, respectively). Of the dimensions of Harm avoidance, Anticipatory worry and Fatigability had the strongest effects. Symptoms of depression and anxiety showed very similar underlying temperament patterns. Limitations Although Harm avoidance and Pessimism appear to be important endophenotype candidates for depression and anxiety, their potential usefulness as endophenotypes, and whether they meet all the suggested criteria for endophenotypes will remain to be confirmed in future studies. Conclusions Personality characteristics of Pessimism and Harm avoidance, in particular its dimensions Anticipatory worry and Fatigability, are strongly related to symptoms of depression and anxiety as well as to depressive disorder in this population. These temperamental features may be used as dimensional susceptibility factors in etiological studies of depression, which may aid in the development of improved clinical practice.

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 β-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.

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.

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 β=0.056 for rs5993883–rs2239393–rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and β=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 β=0.0023; p=0.00005 and β=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., Article summary Article focus Impact on depression of monoaminergic candidate genes with prior evidence of gene–environment interaction for affective disorders, and of dopamine receptor genes. Gene–environment and gene–gender interactions in the aetiology of depression. Effect of measures of early development and of social environment on depression. Key messages Genes of monoamine neurotransmission play a role in the aetiology of depression conditional on environmental risk, especially in males and in individuals at high early developmental risk group; in particular, there is evidence of an interaction with a COMT high-risk haplotype including Val158. Gender-specific mechanisms and responses to environmental effectors are evident in the regulation of mood. Strengths and limitations of this study Depression as defined does not necessarily imply clinical diagnosis of major depression but is based on a self-report or Hopkins Symptom Check List-25 score. Despite this, the prevalence of depressed mood was in the same range as that in earlier reports. There was a notable drop-out rate of about half of the original cohort members. The choice of measures of early development and of social environment was limited by the availability of variables collected. Advantages include the availability of longitudinal follow-up data starting antenatally, enabling inclusion of the environmental dimension without recall bias. The cohort’s unique genetic structure with isolation and more genetic homogeneity permits identification of genetic-risk loci that may be missed when using more heterogeneous populations. The subjects are representative of the population, with all cohort members born in the same year and within a geographically defined area. The study sample’s size is sufficient for identifying genetic variants of moderate impact. Both genders are represented in almost equal amounts; gender differences exist in both depression and temperament traits such as harm avoidance. As the sample is a 1-year birth cohort, genetic effects may be isolated from the effects of ageing; some psychiatric traits such as harm avoidance are age-dependent.

The clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic–pituitary–adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population-based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation-based allelic association analysis of a sample of 1,654 adults recruited from Finland's population-based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex-dependent and symptom-specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes. © 2009 Wiley-Liss, Inc.

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.

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genome-wide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q.

Background: The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5 ) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD. Methods: The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and casecontrol samples, were used for replication. Results: Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost sixfold risk for MDD (OR 5.74, 95%CI 3.12-10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT). Conclusions: Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD. © 2014 Korhonen et al.