Emma Nyman

A Population-Based Association Study of Candidate Genes for Depression and Sleep Disturbance

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 Finlands 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.

Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background

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.

Impact of temperament on depression and anxiety symptoms and depressive disorder in a population-based birth cohort

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.

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 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.

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 Cloningers 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 Association between DRD2/ANKK1 and Genetically Informed Measures of Alcohol Use and Problems

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 Mälmö‐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.

The association between DRD2/ANKK1 and genetically informed measures of alcohol use and problems

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 Mälmö‐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.

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.

Role of nicotine dependence in the association between the Dopamine Receptor Gene DRD3 and major depressive disorder

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 case-control 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 six-fold 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.