Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

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

Smoking status as a potential confounder in the study of brain structure in schizophrenia

Several but not all MRI studies have reported volume reductions in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia. Given the high prevalence of smoking among schizophrenia patients and the fact that smoking has also been associated with alterations in brain morphology, this study evaluated whether a proportion of the known gray matter reductions in key brain regions may be attributed to smoking rather than to schizophrenia alone.We examined structural MRI data of 112 schizophrenia patients (53 smokers and 59 non-smokers) and 77 healthy non-smoker controls collected by the MCIC study of schizophrenia. An automated atlas based probabilistic method was used to generate volumetric measures of the hippocampus and DLPFC. The two patient groups were matched with respect to demographic and clinical variables.Smoker schizophrenia patients showed significantly lower hippocampal and DLPFC volumes than non-smoker schizophrenia patients. Gray matter volume reductions associated with smoking status ranged between 2.2% and 2.8%. Furthermore, we found significant volume differences between smoker patients and healthy controls in the hippocampus and DLPFC, but not between non-smoker patients and healthy controls.Our data suggest that a proportion of the volume reduction seen in the hippocampus and DLPFC in schizophrenia is associated with smoking rather than with the diagnosis of schizophrenia. These results may have important implications for brain imaging studies comparing schizophrenia patients and other groups with a lower smoking prevalence

Prefrontal inefficiency is associated with polygenic risk for schizophrenia

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants

Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia

<div><p></p><p><i>Objectives.</i> Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. <i>Methods.</i> Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. <i>Results.</i> No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10^–8) in our GWA study, but 10 SNPs reached <i>P</i>-values less than 10^–6. The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. <i>Conclusions.</i> Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.</p></div

PALVELUTUOTTEEN HINNOITTELUN KEHITTÄMINEN

Tämän opinnäytetyön aiheena on palvelutuotteen hinnoittelun kehittäminen. Tutkimuksen kohteena on Tili- ja isännöitsijätoimisto Ky. Tili- ja isännöitsijätoimisto Ky on Vaasassa toimiva tili- ja isännöintitoimisto, joka tarjoaa taloushallinto- ja isännöintipalveluita yrityksille. Tutkimuksen tavoitteena on kehittää Tili- ja isännöitsijätoimisto Ky:n isännöitsijän palvelutuotteiden hinnoittelua. Hinnoittelumenetelmäksi valittiin toimintoperusteinen hinnoittelu, jonka lähtökohtana on selvittää asiakaskohtaisia välillisiä kustannuksia. Kysymys oli suorite-kohtaisten kustannusten laskemisesta, eli toimintoperusteisesta prosessilaskennasta. Toimintoperusteinen prosessilaskenta tukee hinnoittelun päätöstä. Toiminto-analyysin jälkeen selvitettiin resurssien kohdistumista yrityksen eri toiminnoille. Aluksi selvitettiin yrityksen kustannusajuri, jonka perusteella kustannukset on kohdistettu eri toiminnoille. Seuraavaksi selvitettiin toimintoajurin avulla toimintoihin liittyvät yksikkökustannukset. Tuotteiden hinnoittelussa myyntihinnan on tarkoituksena sisältää kaikkien kustannusten lisäksi voittotavoite. Tutkimuksen teoriaosuuden keskeisiä asioita ovat toimintoperusteisen kustannuslaskennan, sekä hinnoittelun perusteiden esittely. Niiden avulla voidaan perustella hinnoittelupäätöstä tukeva toimintolaskenta. Opinnäytetyössä esitellään lisäksi kustannusperusteista hinnoittelua sekä isännöintiä ja tilitoimistoa yleisesti. Tutkimusmenetelmänä käytettiin kvalitatiivista eli laadullista tutkimusta. Tutkimuksen teoriaosuuteen käytettiin toimintolaskennan, taloushallinnon alan sekä hinnoittelun teoriaan liittyvää kirjallisuutta. Aineistonkeruussa havainnoitiin yrityksen tilinpäätöstä vuodelta 2016 ja yrityksen toimintaa liittyviä ohjelmia sekä tietokantoja. Lisäksi haastateltiin Tili- ja isännöitsijätoimisto Ky:n omistajaa ja työntekijöitä.This research was designed to develop the used pricing method for the case firm Tili- ja isännöitsijätoimisto Ky. The main area of this research focused on the main service products in property management. The case firm offers financial accounting and management services to house companies and other customer companies. Activity based costing was selected as the new pricing method in order to identify the customer-specific indirect costs. The aim of activity-based costing was to support pricing decisions for the case firm. In the implementation steps, activities must be identified first, and then the process continues with an activity analysis. Once the costs of activity and its drivers have been identified and its costs have been determined, then the costs of activity is allocated to the service product. In the allocation process, when the activity driver has been determined, the cost per unit can then be determined. Once the product cost per unit has been determined then the case firm considers the generated value of its service product, so the pricing of all the service product sales cover the fixed expenses with any remaining contribution margin providing profits. The theoretical study of this thesis introduced activity based costing and pricing to support activity based cost implementation and pricing decisions. In addition, it introduced cost based pricing and property management business and accounting firms in general. This research was implemented using the qualitative research method. The research material consists of related activity based costing, financial management, management accounting and pricing literature. The theoretical information was gathered from scientific research, academic books and some material was collect-ed from the Internet. The empirical data in this research was gathered by observing the case company’s financial statement from the year 2016 together with some business activities related programs and databases. In addition, was collected by interviewing the case company owner and the other employers of the company