Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

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

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Suunnannäyttäjät – Tapiola-ryhmän kehitysyhteisö

Tässä opinnäytetyössä tarkastellaan suomalaisen finanssiyhtiön Tapiola-ryhmän asiakasyhteisöä. Sen tarkoitus on selvittää asiakasyhteisön jäsenien rakenne ja heidän avullaan selvittää, miten asiakasyhteisön jäsenet haluaisivat itse kehittää asiakasyhteisön toimintaa. Jotta asiakasyhteisö toimisi käyttäjäkeskeisesti ja olisi käyttäjiensä muokkaama, on tarpeellista selvittää mitä asiakasyhteisön jäsenet haluavat asiakasyhteisössä tehdä ja minkälainen he haluavat sen olevan. Opinnäytetyötä varten tehtiin asiakasyhteisön valituille jäsenille tutkimus, jossa selvitettiin muotoilupelin avulla miten tutkittavat haluaisivat muuttaa asiakasyhteisön toimintaa. Tutkimuskysymys muotoiltiin yhdessä Tapiola-ryhmän kanssa. Tutkimuksessa tehtiin haastatteluja asiakasyhteisön jäsenille ja haastattelujen yhteydessä haastateltavat osallistuivat muotoilupeliin, jonka tarkoituksena oli selvittää miten he haluaisivat muokata asiakasyhteisöä. Muotoilupelissä haastateltavat ottivat kantaa siihen, mitä elementtejä he haluaisivat asiakasyhteisössä olevan. Tutkimuksessa käytettiin perinteistä haastattelua ja osallistavaa muotoilupeliä. Haastateltavat eivät tunteneet käytettävää menetelmää entuudestaan, vaan he osallistuivat peliin käyttäjinä. Muotoilupelin tuloksia tutkittiin erillisenä osana haastatteluista Affinity Diagrammilla. Tuloksia tulkittaessa selveni, että peliosion toista osaa voitiin tulkita Affinity Diagrammilla, mutta toista osaa ei pystytty tulkitsemaan Affinty Diagrammin avulla. Tutkimuksen tuloksien perusteella voidaan todeta että Tapiola-ryhmän asiakasyhteisön Suunnannäyttäjien perustoiminnot ovat jäsenten mielestä hyvä perusta, mutta asiakasyhteisöstä puuttuu vielä sellaiset elementit, joista asiakasyhteisön jäsenet kokisivat saavansa lisäarvoa. Haastateltavat kaipaisivat asiakasyhteisöön sellaisia elementtejä, jotka mahdollistavat asiakasyhteisön jäsenten kanssakäymisen toistensa kanssa. Tutkimuksen tuloksia hyödynnetään Tapiola-ryhmässä asiakasyhteisön kehittämistyössä. Tuloksia voidaan myös hyödyntää muiden asiakasyhteisöjen kehitystyössä.Suunnannäyttäjät – Tapiola Groups development community This thesis focuses on a customer community of a Finnish financial company, Tapiola Group. The purpose is to find out the construction of the community and with the help of the users find out how they would like to develop the community’s activities. In order to act as a user centered community and be molded by its users, it is necessary to find out what they want to do in the community and what kind do they want it to be. A study was done for this thesis to chosen members of the community. The chosen method was a design game, through which investigated how the members would develop the community. The focus of the study was done with Tapiola Group. The study was done with traditional interviews and by a design game, which purpose was to find out how the members would like to develop and change the community. In the design game the members told which elements the members would like to have in the community. The study was done with a traditional interview and a participatory design game. The members didn’t know the method in forehand, but participated as users of the game. The results of the design game were interpreted as a separate part from the interviews by an Affinity diagram. When the results were analyzed, it was realized that the first part of the game could be interpreted by an Affinity Diagram, but the second part couldn’t. The results show that the basic functions of the community make a good foundation for the community, but the community still lacks the elements which would make the members feel like they would gain added value. The members would like the community to have more elements which would allow more interaction with other members. The results of this thesis will be used to develop the community even further. The results may even be used to develop other communities