Innovaatiokeskus Kainuuseen:rakennettu ympäristö ja identiteetti

Tiivistelmä. Tämä suunnitelmapainotteinen diplomityö on toteutettu yhteistyössä Kajaanin kaupungin kanssa. Diplomityöni on tarkoitus toimia taustatekijänä suunnittelualueen tulevassa kaavamuutoksessa. Ulkopuolisena asiantuntijana työlläni toimii Kajaanin kaupunginarkkitehti Anne Siltavuori. Kajaanin joen ja rauniolinnan välittömässä läheisyydessä sijaitsee nykyisellään Kajaanin Vanha kirjastotalo. Alueelle on suunnitteilla kaavamuutos, jossa Vanha kirjastotalo suojellaan ja sen nykyiseen rakennusmassaan nähden suuri tontti jaetaan kahdeksi erilliseksi tontiksi. Syntyvälle tontille kaavaillaan alueen arvoille ja identiteetille sekä Kajaanin kaupunkikuvaan sopivaa uudisrakentamista. Diplomityöni sisältönä on luoda konseptitasoinen luonnossuunnitelma tontille sijoittuvasta uudisrakennuksesta. Kajaanin kaupungin mukaan uudisrakennukseen olisi hyvä sijoittaa ainakin osin asumista. Diplomityössäni halusin esittää, että asuminen ei kuitenkaole rakennuksen ainoa käyttötarkoitus. Suunnitelmani keskittyy rakennuksen arkkitehtonisesti erinomaisten suunnitteluratkaisujen ja sen käyttötarkoituksen löytämiseen sekä näiden tekijöiden yhteensovittamiseen alueellista identiteettiä tukien. Työhöni sisältyy myös kirjallinen teoriaosuus, joka käsittelee arkkitehtuurin ja identiteetin suhdetta alueellisen identiteetin näkökulmasta. Tätä seuraa paikan identiteetin analyysi, jossa pureudutaan suunnittelualueen identiteettiin alueen historian kautta.Innovation center to Kainuu : built environment and identity. Abstract. This diploma thesis is a design project that has been conducted in collaboration with the city of Kajaani. The purpose of my thesis is to be enclosed in the upcoming alteration of the town plan affecting the site. The city architect of Kajaani Anne Siltavuori has acted as a third party consultant for this thesis. The old library of Kajaani is located nearby the Kajaani River and the ruins of the Kajaani Castle. The plan regarding the area is about to undergo an alteration process, during which the old library building will be conservated, and its vast site divided into two separate plots. The aim of the newbuild situated on the new site is to fit in with the identity and values of the surrounding area, as well as the cityscape of Kajaani. The intention of this diploma thesis is to create a concept design for a new building on the site. The city of Kajaani suggests the building should consist at least partly of housing, but in my thesis I wanted to show that it shouldn’t be its only purpose. The focus of the diploma thesis is to achieve and combine an outstanding architectural design solution and a suitable use for the building, while embracing the area’s regional identity. The thesis contains a written theory analysis which discusses the relation between architecture and identity in a regional framework. The discussion is followed by an analysis of the sense of place, which is evaluated considering the site’s history

A partial loss-of-function variant in AKT2 is associated with reduced insulin-mediated glucose uptake in multiple insulin-sensitive tissues: A genotype-based callback positron emission tomography study

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM) study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues—skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)—and increases of 16.8–19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers

A Partial Loss-of-Function Variant in AKT2 is Associated with Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin Sensitive Tissues: a Genotype-Based Callback Positron Emission Tomography Study

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of p.Pro50Thr on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated.  We identified carriers (N=20) and matched non-carriers (N=25) for this allele in the population-based METSIM study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to non-carriers, we found a 39.4% reduction in whole body GU (P=0.006) and a 55.6% increase in the rate of endogenous glucose production (P=0.038). We found significant reductions in GU in multiple tissues: skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%), and increases of 16.8-19.1% in 7 tested brain regions. These data demonstrate that the P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin sensitive tissues, and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers.</p

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe