Genetic Mechanisms Underlying Autism Spectrum Disorders

Autism is a childhood-onset developmental disorder characterized by deficits in reciprocal social interaction, verbal and non-verbal communication, and dependence on routines and rituals. It belongs to a spectrum of disorders (autism spectrum disorders, ASDs) which share core symptoms but show considerable variation in severity. The whole spectrum affects 0.6-0.7% of children worldwide, inducing a substantial public health burden and causing suffering to the affected families. Despite having a very high heritability, ASDs have shown exceptional genetic heterogeneity, which has complicated the identification of risk variants and left the etiology largely unknown. However, recent studies suggest that rare, family-specific factors contribute significantly to the genetic basis of ASDs. In this study, we investigated the role of DISC1 (Disrupted-in-schizophrenia-1) in ASDs, and identified association with markers and haplotypes previously associated with psychiatric phenotypes. We identified four polymorphic micro-RNA target sites in the 3 UTR of DISC1, and showed that hsa-miR-559 regulates DISC1 expression in vitro in an allele-specific manner. We also analyzed an extended autism pedigree with genealogical roots in Central Finland reaching back to the 17th century. To take advantage of the beneficial characteristics of population isolates to gene mapping and reduced genetic heterogeneity observed in distantly related individuals, we performed a microsatellite-based genome-wide screen for linkage and linkage disequilibrium in this pedigree. We identified a putative autism susceptibility locus on chromosome 19p13.3 and obtained further support for previously reported loci at 1q23 and 15q11-q13. To follow-up these findings, we extended our study sample from the same sub-isolate and initiated a genome-wide analysis of homozygosity and allelic sharing using high-density SNP markers. We identified a small number of haplotypes shared by different subsets of the genealogically connected cases, along with convergent biological pathways from SNP and gene expression data, which highlighted axon guidance molecules in the pathogenesis of ASDs. In conclusion, the results obtained in this thesis show that multiple distinct genetic variants are responsible for the ASD phenotype even within single pedigrees from an isolated population. We suggest that targeted resequencing of the shared haplotypes, linkage regions, and other susceptibility loci is essential to identify the causal variants. We also report a possible micro-RNA mediated regulatory mechanism, which might partially explain the wide-range neurobiological effects of the DISC1 gene.

Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line

Background: Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging. Methods: We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations. Results: This integrated genomic approach led to the identification of RIC8A at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for RIC8A mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of RIC8A transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low RIC8A expression and the presence of TP53 mutations (P = 0.006). Conclusion: We demonstrate a data integration strategy leading to the identification of RIC8A as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as in vivo evidence of loss of RIC8A expression in a subgroup of aggressive TP53 mutant breast cancers.

Using IRAP markers for analysis of genetic variability in populations of resource and rare species of plants

Species specific LTR retrotransposons were first cloned in five rare relic species of drug plants located in the Perm’ region. Sequences of LTR retrotransposons were used for PCR analysis based on amplification of repeated sequences from LTR or other sites of retrotransposons (IRAP). Genetic diversity was studied in six populations of rare relic species of plants Adonis vernalis L. by means of the IRAP method; 125 polymorphic IRAP markers were analyzed. Parameters for DNA polymorphism and genetic diversity of A. vernalis populations were determined.

Using IRAP markers for analysis of genetic variability in populations of resource and rare species of plants

Species specific LTR retrotransposons were first cloned in five rare relic species of drug plants located in the Perm’ region. Sequences of LTR retrotransposons were used for PCR analysis based on amplification of repeated sequences from LTR or other sites of retrotransposons (IRAP). Genetic diversity was studied in six populations of rare relic species of plants Adonis vernalis L. by means of the IRAP method; 125 polymorphic IRAP markers were analyzed. Parameters for DNA polymorphism and genetic diversity of A. vernalis populations were determined.

Identification of genetic susceptibility loci for migraine

Migraine is the common cause of chronic episodic headache, affecting 12%-15% of the Caucasian population (41 million Europeans and some half a million Finns), and causes considerable loss of quality of life to its sufferers, as well as being linked to increased risk for a wide range of conditions, from depression to stroke. Migraine is the 19th most severe disease in terms of disability-adjusted life years, and 9th among women. It is characterized by attacks of headache accompanied by sensitivity to external stimuli lasting 4-72 hours, and in a third of cases by neurological aura symptoms, such as loss of vision, speech or muscle function. The underlying pathophysiology, including what triggers migraine attacks and why they occur in the first place, is largely unknown. The aim of this study was to identify genetic factors associated with the hereditary susceptibility to migraine, in order to gain a better understanding of migraine mechanisms. In this thesis, we report the results of genetic linkage and association analyses on a Finnish migraine patient collection as well as migraineurs from Australia, Denmark, Germany, Iceland and the Netherlands. Altogether we studied genetic information of nearly 7,000 migraine patients and over 50,000 population-matched controls. We also developed a new migraine analysis method called the trait component analysis, which is based on individual patient responses instead of the clinical diagnosis. Using this method, we detected a number of new genetic loci for migraine, including on chromosome 17p13 (HLOD 4.65) and 10q22-q23 (female-specific HLOD 7.68) with significant evidence of linkage, along with five other loci (2p12, 8q12, 4q28-q31, 18q12-q22, and Xp22) detected with suggestive evidence of linkage. The 10q22-q23 locus was the first genetic finding in migraine to show linkage to the same locus and markers in multiple populations, with consistent detection in six different scans. Traditionally, ion channels have been thought to play a role in migraine susceptibility, but we were able to exclude any significant role for common variants in a candidate gene study of 155 ion transport genes. This was followed up by the first genome-wide association study in migraine, conducted on 2,748 migraine patients and 10,747 matched controls followed by a replication in 3,209 patients and 40,062 controls. In this study, we found interesting results with genome-wide significance, providing targets for future genetic and functional studies. Overall, we found several promising genetic loci for migraine providing a promising base for future studies in migraine.

Identifying Genetic Risk Factors in Canine Autoimmune Disorders

Autoimmune diseases are more common in dogs than in humans and are already threatening the future of some highly predisposed dog breeds. Susceptibility to autoimmune diseases is controlled by environmental and genetic factors, especially the major histocompatibility complex (MHC) gene region. Dogs show a similar physiology, disease presentation and clinical response as humans, making them an excellent disease model for autoimmune diseases common to both species. The genetic background of canine autoimmune disorders is largely unknown, but recent annotation of the dog genome and subsequent development of new genomic tools offer a unique opportunity to map novel autoimmune genes in various breeds. Many autoimmune disorders show breed-specific enrichment, supporting a strong genetic background. Furthermore, the presence of hundreds of breeds as genetic isolates facilitates gene mapping in complex autoimmune disorders. Identification of novel predisposing genes establishes breeds as models and may reveal novel candidate genes for the corresponding human disorders. Genetic studies will eventually shed light on common biological functions and interactions between genes and the environment. This study aimed to identify genetic risk factors in various autoimmune disorders, including systemic lupus erythematosus (SLE)-related diseases, comprising immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis arteritis (SMRA) as well as Addison s disease (AD) in Nova Scotia Duck Tolling Retrievers (NSDTRs) and chronic superficial keratitis (CSK) in German Shepherd dogs (GSDs). We used two different approaches to identify genetic risk factors. Firstly, a candidate gene approach was applied to test the potential association of MHC class II, also known as a dog leukocyte antigen (DLA) in canine species. Secondly, a genome-wide association study (GWAS) was performed to identify novel risk loci for SLE-related disease and AD in NSDTRs. We identified DLA risk haplotypes for an IMRD subphenotype of SLE-related disease, AD and CSK, but not in SMRA, and show that the MHC class II gene region is a major genetic risk factor in canine autoimmune diseases. An elevated risk was found for IMRD in dogs that carried the DLA-DRB1*00601/DQA1*005011/DQB1*02001 haplotype (OR = 2.0, 99% CI = 1.03-3.95, p = 0.01) and for ANA-positive IMRD dogs (OR = 2.3, 99% CI = 1.07-5.04, p-value 0.007). We also found that DLA-DRB1*01502/DQA*00601/DQB1*02301 haplotype was significantly associated with AD in NSDTRs (OR = 2.1, CI = 1.0-4.4, P = 0.044) and the DLA-DRB1*01501/DQA1*00601/DQB1*00301 haplotype with the CSK in GSDs (OR=2.67, CI=1.17-6.44, p= 0.02). In addition, we found that homozygosity for the risk haplotype increases the risk for each disease phenotype and that an overall homozygosity for the DLA region predisposes to CSK and AD. Our results have enabled the development of genetic tests to improve breeding practices by avoiding the production of puppies homozygous for risk haplotypes. We also performed the first successful GWAS for a complex disease in dogs. With less than 100 cases and 100 controls, we identified five risk loci for SLE-related disease and AD and found strong candidate genes involved in a novel T-cell activation pathway. We show that an inbred dog population has fewer risk factors, but each of them has a stronger genetic risk. Ongoing studies aim to identify the causative mutations and bring new knowledge to help diagnostics, treatment and understanding of the aetiology of SLE-related diseases.

The Protection of Traditional Knowledge Associated with Genetic Resources: The Role of Databases and Registers

"The Protection of Traditional Knowledge Associated with Genetic Resources: The Role of Databases and Registers" ABSTRACT Yovana Reyes Tagle The misappropriation of TK has sparked a search for national and international laws to govern the use of indigenous peoples knowledge and protection against its commercial exploitation. There is a widespread perception that biopiracy or illegal access to genetic resources and associated traditional knowledge (TK) continues despite national and regional efforts to address this concern. The purpose of this research is to address the question of how documentation of TK through databases and registers could protect TK, in light of indigenous peoples increasing demands to control their knowledge and benefit from its use. Throughout the international debate over the protection of TK, various options have been brought up and discussed. At its core, the discussion over the legal protection of TK comes down to these issues: 1) The doctrinal question: What is protection of TK? 2) The methodological question: How can protection of TK be achieved? 3) The legal question: What should be protected? And 4) The policy questions: Who has rights and how should they be implemented? What kind of rights should indigenous peoples have over their TK? What are the central concerns the TK databases want to solve? The acceptance of TK databases and registers may bring with it both opportunities and dangers. How can the rights of indigenous peoples over their documented knowledge be assured? Documentation of TK was envisaged as a means to protect TK, but there are concerns about how documented TK can be protected from misappropriation. The methodology used in this research seeks to contribute to the understanding of the protection of TK. The steps taken in this research attempt to describe and to explain a) what has been done to protect TK through databases and registers, b) how this protection is taking place, and c) why the establishment of TK databases can or cannot be useful for the protection of TK. The selected case studies (Peru and Venezuela) seek to illustrate the complexity and multidisciplinary nature of the establishment of TK databases, which entail not only legal but also political, socio-economic and cultural issues. The study offers some conclusions and recommendations that have emerged after reviewing the national experiences, international instruments, work of international organizations, and indigenous peoples perspectives. This thesis concludes that if TK is to be protected from disclosure and unauthorized use, confidential databases are required. Finally, the TK database strategy needs to be strengthened by the legal protection of the TK itself.

Analysis of Puumala hantavirus in a bank vole population in northern Finland: evidence for co-circulation of two genetic lineages and frequent reassortment between strains

"In this study, for the first time, two distinct genetic lineages of Puumala virus (PUUV) were found within a small sampling area and within a single host genetic lineage (Ural mtDNA) at Pallasjarvi, northern Finland. Lung tissue samples of 171 bank voles (Myodes glareolus) trapped in September 1998 were screened for the presence of PUUV nucleocapsid antigen and 25 were found to be positive. Partial sequences of the PUUV small (S), medium (M) and large (L) genome segments were recovered from these samples using RT-PCR. Phylogenetic analysis revealed two genetic groups of PUUV sequences that belonged to the Finnish and north Scandinavian lineages. This presented a unique opportunity to study inter-lineage reassortment in PUUV; indeed, 32% of the studied bank voles appeared to carry reassortant virus genomes. Thus, the frequency of inter-lineage reassortment in PUUV was comparable to that of intra-lineage reassortment observed previously (Razzauti, M., Plyusnina, A., Henttonen, H. & Plyusnin, A. (2008). J Gen Virol 89, 1649-1660). Of six possible reassortant S/M/L combinations, only two were found at Pallasjarvi and, notably, in all reassortants, both S and L segments originated from the same genetic lineage, suggesting a non-random pattern for the reassortment. These findings are discussed in connection to PUUV evolution in Fermoscandia."

Origins of the sex differences in handedness and mental rotation ability : genetic, environmental and hormonal effects

In humans, well-replicated and robust sex differences in cognitive functions exist for handedness and mental rotation ability. A common characteristic in human cognitive functions is the lateralization of language functions. Handedness is a common measure of laterality and is related to language lateralization. The prevalence of left-handedness is higher in males than in females, the male to female ratio being about 1.2. Among cognitive abilities, the largest sex difference is evident in the Vandenberg and Kuse Mental Rotation Test (MRT), which requires the ability to rotate objects in mental space. On average, males achieve scores one standard deviation higher than females in the MRT. The present thesis investigated the origins of the sex differences in laterality and spatial ability as represented by handedness and mental rotation ability, respectively. Two population-based Finnish twin cohorts were utilized in this study. Handedness was studied in 25 810 twins and 4068 singletons born before 1958 from the Older Finnish Twin Cohort, and in 4736 twins born in 1983-87 from the FinnTwin12. MRT was studied in a sub-sample of 804 young adult participants from the FinnTwin12 sample. The main findings of this study were: 1) the prevalence of left-handedness was higher among males than among females in both singletons and in twins; 2) males had significantly higher scores than females in MRT; 3) about one quarter of the variance in handedness and about half of the variance in MRT was explained by genetic effects, whereas the remainder of the variance in these traits was explained by environmental effects unique to each individual. The magnitude of the genetic effects was similar in both sexes; 4) left-handedness was significantly less common in female co-twins of a male than in female co-twins of a female, and female co-twins of a male scored significantly higher than did female co-twins of a female in the Mental Rotation Test. This dissertation discusses whether these differences between females from opposite- and same-sex twin pairs are due to the prenatal transfer of testosterone from the male fetus in females with male co-twins or whether they arise from postnatal socialization effects.

Genetic variation in the LDL receptor-related protein 5 (LRP5) gene : Association with bone health and metabolic parameters

Bone mass accrual and maintenance are regulated by a complex interplay between genetic and environmental factors. Recent studies have revealed an important role for the low-density lipoprotein receptor-related protein 5 (LRP5) in this process. The aim of this thesis study was to identify novel variants in the LRP5 gene and to further elucidate the association of LRP5 and its variants with various bone health related clinical characteristics. The results of our studies show that loss-of-function mutations in LRP5 cause severe osteoporosis not only in homozygous subjects but also in the carriers of these mutations, who have significantly reduced bone mineral density (BMD) and increased susceptibility to fractures. In addition, we demonstrated for the first time that a common polymorphic LRP5 variant (p.A1330V) was associated with reduced peak bone mass, an important determinant of BMD and osteoporosis in later life. The results from these two studies are concordant with results seen in other studies on LRP5 mutations and in association studies linking genetic variation in LRP5 with BMD and osteoporosis. Several rare LRP5 variants were identified in children with recurrent fractures. Sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses revealed no disease-causing mutations or whole-exon deletions. Our findings from clinical assessments and family-based genotype-phenotype studies suggested that the rare LRP5 variants identified are not the definite cause of fractures in these children. Clinical assessments of our study subjects with LPR5 mutations revealed an unexpectedly high prevalence of impaired glucose tolerance and dyslipidaemia. Moreover, in subsequent studies we discovered that common polymorphic LRP5 variants are associated with unfavorable metabolic characteristics. Changes in lipid profile were already apparent in pre-pubertal children. These results, together with the findings from other studies, suggest an important role for LRP5 also in glucose and lipid metabolism. Our results underscore the important role of LRP5 not only in bone mass accrual and maintenance of skeletal health but also in glucose and lipid metabolism. The role of LRP5 in bone metabolism has long been studied, but further studies with larger study cohorts are still needed to evaluate the specific role of LRP5 variants as metabolic risk factors.

Determinants of Cognitive Impairment in Old Age and Their Genetic Architecture

Cognitive health is of central importance for independent and balanced old age, while memory disorders represent the leading cause of intensive and long-term care among the Finnish elderly. The aims of this study were to analyse the effect of height, body mass index, weight change, metabolic conditions and coffee drinking in midlife on cognitive performance in old age among a sample of 2606 Finnish twins aged 65 years or older who had participated in a telephone interview to assess their cognitive status. Since coffee drinking associates with several metabolic conditions and Finns are known to be the greatest consumers of coffee in the world, the heritability and stability of coffee drinking was analysed in the whole Older Finnish Twin Cohort (n=10716). In order to investigate the association between height and cognitive performance in a population with more supportive childhood living conditions, a total of 2161 Danish twins were included in this study. A greater height was found to clearly associate with better cognitive performance in Finnish subjects, but less so among the Danish sample, which may reflect the childhood environmental differences between these cohorts. In the Finnish subjects, there was greater variance in cognitive performance among shorter subjects, and environmental factors were found to play a greater role in their cognitive performance, whereas the cognitive performance of taller participants was mainly explained by genetic factors. Midlife metabolic variables that were found to be significantly associated with a poorer cognitive performance in old age included a higher body mass index and three metabolic conditions: cardiovascular disease, hypertension and, most significantly of all, diabetes. Moreover, both weight gain and loss, even to a lesser degree than suggested previously, were found to be associated with poorer cognition. Furthermore, evidence of a causal relationship between midlife cardiovascular disease and cognitive performance in old age was demonstrated among discordant twin pairs. Conversely, no effect of coffee drinking in midlife on cognitive performance in old age was observed, although coffee drinking was demonstrated to be stable in the study population. The heritability of coffee drinking was found to differ across sexes and age groups, being 51% in men and 52% in women in the whole study population. This study supports the contention that cognitive performance in old age reflects the effects of multiple genetic and environmental exposures, including their complex interactions during the life-span. The demonstrated associations and evidence of a causal pathway between potentially preventable exposures and poorer cognitive performance highlight the importance of preventive medicine.

Genetic and epigenetic mechanisms of tumor predisposition in hereditary non-polyposis colorectal carcinoma and sporadic cancers

Individuals with inherited deficiency in DNA mismatch repair(MMR) (Lynch syndrome) LS are predisposed to different cancers in a non-random fashion. Endometrial cancer (EC) is the most common extracolonic malignancy in LS. LS represents the best characterized form of hereditary nonpolyposis colorectal carcinoma (HNPCC). Other forms of familial non-polyposis colon cancer exist, including familial colorectal cancer type X (FCCX). This syndrome resembles LS, but MMR gene defects are excluded and the predisposition genes are unknown so far. To address why different organs are differently susceptible to cancer development, we examined molecular similarities and differences in selected cancers whose frequency varies in LS individuals. Tumors that are common (colorectal, endometrial, gastric) and less common (brain, urological) in LS were characterized for MMR protein expression, microsatellite instability (MSI), and by altered DNA methylation. We also studied samples of histologically normal endometrium, endometrial hyperplasia,and cancer for molecular alterations to identify potential markers that could predict malignant transformation in LS and sporadic cases. Our results suggest that brain and kidney tumors follow a different pathway for cancer development than the most common LS related cancers.Our results suggest also that MMR defects are detectable in endometrial tissues from a proportion of LS mutation carriers prior to endometrial cancer development. Traditionally (complex) atypical hyperplasia has been considered critical for progression to malignancy. Our results suggest that complex hyperplasia without atypia is equally important as a precursor lesion of malignancy. Tumor profiles from Egypt were compared with colorectal tumors from Finland to evaluate if there are differences specific to the ethnic origin (East vs.West). Results showed for the first time a distinct genetic and epigenetic signature in the Egyptian CRC marked by high methylation of microsatellite stable tumors associated with advanced stage, and low frequency of Wnt signaling activation, suggesting a novel pathway. DNA samples from FCCX families were studied with genome wide linkage analysis using microsatellite markers. Selected genes from the linked areas were tested for possible mutations that could explain predisposition to a large number of colon adenomas and carcinomas seen in these families. Based on the results from the linkage analysis, a number of areas with tentative linkage were identified in family 20. We narrowed down these areas by additional microsatellite markers to found a mutation in the BMPR1A gene. Sequencing of an additional 17 FCCX families resulted in a BMPR1A mutation frequency of 2/18 families (11%). Clarification of the mechanisms of the differential tumor susceptibility in LS increases the understanding of gene and organ specific targets of MMR deficiency. While it is generally accepted that widespread MMR deficiency and consequent microsatellite instability (MSI) drives tumorigenesis in LS, the timing of molecular alterations is controversial. In particular, it is important to know that alterations may occur several years before cancer formation, at stages that are still histologically regarded as normal. Identification of molecular markers that could predict the risk of malignant transformation may be used to improve surveillance and cancer prevention in genetically predisposed individuals. Significant fractions of families with colorectal and/or endometrial cancer presently lack molecular definition altogether. Our findings expand the phenotypic spectrum of BMPR1A mutations and, for the first time, link FCCX families to the germline mutation of a specific gene. In particular, our observations encourage screening of additional families with FCCX for BMPR1A mutation, which is necessary in obtaining a reliable estimate of the share of BMPR1A-associated cases among all FCCX families worldwide. Clinically, the identification of predisposing mutations enables targeted cancer prevention in proven mutation carriers and thereby reduces cancer morbidity and mortality in the respective families.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.

Hostility: A prospective study of the genetic and environmental background and associations with cardiovascular risk

Hostility is a multidimensional construct having wide effects on society. In its different forms, hostility is related to a large array of social and health problems, such as criminality, substance abuse, depression, and cardiovascular risks. Identifying and tackling early-life factors that contribute to hostility may have public health significance. Although the variance in hostility is estimated to be 18-50 percent heritable, there are significant gaps in knowledge regarding the molecular genetics of hostility. It is known that a cold and unsupportive home atmosphere in childhood predicts a child s later hostility. However, the long-term effects of care-giving quality on hostility in adulthood and the role of genes in this association are unclear. The present dissertation is part of the ongoing population-based prospective Young Finns study, which commenced in 1980 with 3596 3-18-year-old boys and girls who were followed for 27 years. The specific aims of the dissertation were first to study the antecedents of hostility by looking at 1) the genetic background, 2) the early environmental predictors, and 3) the gene environment interplay behind hostility. As a second aim, the thesis endeavored to examine 4) the association between hostility and cardiovascular risks, and 5) the moderating effect of demographic factors, such as gender and socioeconomic status, on this association. The study found potential gene polymorphisms from chromosomes 7, 14, 17, and 22 suggestively associated with hostility. Of early environmental influences, breastfeeding and early care-giving were found to predict hostility in adulthood. In addition, a serotonin receptor 2A polymorphism rs6313 moderated the effect of early care-giving on later hostile attitudes. Furthermore, hostility was shown to predict cardiovascular risks, such as metabolic syndrome and inflammation. Finally, parental socioeconomic status was found to moderate the association between anger and early atherosclerosis. The new genetic and early environmental antecedents of hostility identified in this research may help in understanding the development of hostility and its health risks, and in planning appropriate prevention. The significance of early influences on this development is stressed. Although the markers studied are individual- and family-related factors, these may be influenced at the societal level by giving accurate information to all individuals concerned and by improving the societal circumstances.