Abstract Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied further. / Tiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan.

Abstract Bronchiolitis is an infection of the small airways of the lung and is a common reason for infant hospitalizations. The most common causative pathogen is the respiratory syncytial virus (RSV). Genetic factors are thought to influence the risk of bronchiolitis, and better knowledge of bronchiolitis genetics will likely help to elucidate the disease process. Severe bronchiolitis in childhood may predispose to asthma. Therefore, an effective treatment of bronchiolitis may affect the present-day as well as lifelong respiratory health. In this project, we aimed to identify genetic loci of bronchiolitis susceptibility by a genome-wide association study (GWAS) and suitable follow-up studies, and to study a previously asthma-associated CDHR3 variant for association across five bronchiolitis populations by meta-analysis. We performed the GWAS on a Finnish-Swedish case-control population and identified several loci below the suggestive genome-wide significance level. Of these, three variants showed nominal associations in a replication population from the Netherlands. One of the loci affected KCND3 expression, and two others were intergenic variants with putative regulatory potential. In a follow-up study conducted on a GWAS sub population, we identified the NKG2D locus as a candidate of susceptibility to bronchiolitis. The genomic region encompassing NKG2D variants was reportedly associated with NKG2D mRNA and protein abundance. We validated the association between NKG2D genotypes and protein expression with flow cytometry. The association between NKG2D and bronchiolitis was supported by a Finnish replication study. The meta-analysis was performed on populations from Denmark, Finland, Sweden, Germany, and the Netherlands. A potential virus-specific role for the CDHR3 variant was detected in a population that comprised mostly RSV-negative cases. In conclusion, we identified new candidates of bronchiolitis susceptibility in GWAS and subsequent studies. We found the CDHR3 variant was a potential susceptibility factor in severe non-RSV bronchiolitis and asthma. Our preliminary results provide interesting starting points for further studies. In the future, better understanding of the disease mechanisms and the relationship of bronchiolitis and asthma could provide means to design new therapeutic options. / Tiivistelmä Bronkioliitti on viruksen aiheuttama alahengitystieinfektio, joka usein johtaa pienten lasten sairaalahoitoon. Yleisin bronkioliitin aiheuttaja lapsilla on respiratory syncytial -virus (RSV). Perintötekijöiden arvellaan altistavan bronkioliitille, joten uusi tieto altistavista geeneistä voi auttaa ymmärtämään taudin taustalla olevia biologisia mekanismeja. Lapsuusiän bronkioliitin ajatellaan voivan altistaa astmalle, joten bronkioliitin tehokas hoito voi vaikuttaa merkittävästi hengitysterveyteen myös pitkällä aikavälillä. Työssä pyrittiin selvittämään lapsuusajan bronkioliitille altistavia geneettisiä tekijöitä genominlaajuisella assosiaatiokartoituksella, joka toteutettiin suomalais-ruotsalaisessa tapaus-verrokkiväestössä. Löydökset pyrittiin varmentamaan soveltuvilla jatkotutkimuksilla. Lisäksi tarkastelimme astmalle altistavaa CDHR3-geenin polymorfismia viidessä eurooppalaisessa bronkioliittikohortissa käyttäen meta-analyysia. Assosiaatiokartoituksessa havaittiin useita mahdollisia bronkioliittialttiuteen vaikuttavia geenikohtia. Näistä kolme sai tukea hollantilaisessa väestössä tehdyssä assosiaatioanalyysissä, jossa testattiin assosiaatiokartoituksen lupaavimmat löydökset. Yksi altistavista polymorfismeista vaikutti KCND3-geenin ilmentymiseen, ja kaksi muuta olivat geenien välisiä, mahdollisesti geeninsäätelyyn osallistuvia variantteja. Assosiaatiokartoituksen osa-analyysissä NKG2D tunnistettiin mahdolliseksi bronkioliitille altistavaksi geeniksi. NKG2D-immuunireseptorin alentunut ilmentyminen voi tulostemme perusteella altistaa vakavalle bronkioliitille. Meta-analyysissä, jonka tutkimuskohortit olivat peräisin Tanskasta, Suomesta, Ruotsista, Saksasta ja Hollannista, todettiin mahdollinen yhteys CDHR3-geenin polymorfismin ja muun viruksen kuin RSV:n aiheuttaman bronkioliitin välillä. Toteutimme tässä työssä ensimmäisen genominlaajuisen bronkioliittialttiutta koskevan assosiaatiokartoituksen. Assosiaatiokartoituksessa, sitä seuranneissa jatkotutkimuksissa ja meta-analyysissä tunnistimme useita lupaavia alttiusgeenejä, mutta tuloksemme vaativat varmentamista suuremmissa tutkimusväestöissä.

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10−6 and 8.3×10−7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.

Worldwide, alcohol is the third leading risk factor for disease burden, while its harmful use leads to 2.5 million deaths every year. Alcohol dependence (AD) is a complex disease, with devastating effects on individuals, families, and society. It is estimated that 76.3 million people worldwide have suffered from alcohol use disorders (AUD), including alcohol abuse and AD. Alcohol withdrawal or alcohol withdrawal symptom (AWS) refers to a cluster of symptoms that may occur when a heavy drinker suddenly stops or significantly reduces their alcohol intake. These symptoms can start as early as 2 h after the last drink, persist for weeks, and range from mild anxiety and shakiness to severe complications, such as seizures and delirium tremens. Family, twin, and adoption studies have indicated that genetic and environmental factors and their interactions contribute to the development of AD and related phenotypes, with a heritability coefficient of more than 0.5 for AD. Whole-genome linkage and candidate gene association studies have successfully identified several chromosome regions and genes that are related to AD and AWS. Furthermore, gene expression analysis, epigenetic studies, and genome-wide association studies (GWAS) have provided regions and loci for AWS. This chapter reviews the recent findings in genetic studies of AWS.

No description available.

No description available.

Bermudagrass (Cynodon spp.) breeding and cultivar development is hampered by limited information regarding its genetic and phenotypic diversity. A germplasm collection of 206 bermudagrass accessions from 29 countries was genotyped with high-throughput genotyping-by-sequencing technique. Genomic diversity in this diverse germplasm panel was assessed with multifaceted approaches including population structure, phylogenetic analysis, principal component analysis, and genetic diversity parameters. This study revealed substantial genetic variation in the Cynodon accessions, demonstrating the potential of this germplasm panel for further genetic studies and cultivar development in breeding programs. Another critical issue in turfgrass breeding is the lack of information regarding the genetic architecture of traits. Four agronomic traits leaf length, leaf width, internode distance and stem diameter were evaluated in a germplasm panel of common bermudagrass accessions. Then genome-wide association study was performed to dissect the genetic basis of the traits.

Flax (Linum usitatissimum L.) is a self-pollinated crop widely cultivated for fiber and oil production. Flaxseed is renowned for its health attributes but the presence of compounds, such as the heavy metal cadmium (Cd), is undesirable. Genomic studies in flax have produced large amounts of data in the last 15 years, providing useful resources to improve the genetic of this crop using genomics-based technologies and strategies. The goal of this thesis is therefore to capitalize on these advances to address the Cd problem and to propose solutions to improve breeding efficiencies. To find genomic-based solutions to Cd content, to the currently low breeding efficiency and to abiotic stress resistance in flax, this study utilized four major strategies: (1) genomic cross prediction, (2) gene family identification, (3) genome-wide association study (GWAS) and (4) genomic selection (GS). Characterization of the ATP-binding cassette (ABC) transporter and heavy metal associated (HMA) gene families was performed using the flax genome sequence. A total of 198 ABC transporter and 12 HMA genes were identified in the flax genome, of which nine were orthologous to Cd-associated genes in Arabidopsis, rice and maize. A transcriptomic analysis of eight tissues provided some support towards the functional annotation of these genes and confirmed the expression of these ABC transporter and HMA genes in flax seeds and other tissues. A diversity panel of 168 flax accessions was grown in the field at multiple locations and years and the seed content of 24 heavy metals (HMs) was measured. The panel was also sequenced and a single nucleotide polymorphism (SNP) dataset of nearly 43,000 SNPs was defined. A GWAS was conducted using these genotypic and phenotypic data and a total of 355 non-redundant quantitative trait nucleotides (QTNs) were identified for ten of the 24 metal contents. Overall, a total of 24 major and 331 minor effect QTNs were detected, including 11 that were pleiotropic. After allelic tests, 108 non-redundant QTNs were retained for eight of the ten metals and ranging from one for copper (Cu) to 70 for strontium (Sr). A total of 20 candidate genes for HM accumulation were identified at 12 of the 24 major QTN loci, of which five belonged to the ABC transporter family. Many of the metal contents, including Cd, appeared to be controlled by many genes of small effects; hence, GS is better suited than marker-assisted selection for application in breeding. To test this, predictive ability using ten GS statistical models was evaluated using trait-specific QTN and the random genome-wide 43K SNP datasets. Significantly higher predictive abilities were observed from the GS models built with the dataset made of QTNs associated with metal contents (70-80%) compared to that of the 43K dataset (10-25%). This study showed the feasibility of using GS to improve the predictive ability of polygenic traits such as metal content in seeds. GS can be applied in early generation selection to accelerate the improvement of abiotic stress resistance and either select low-Cd lines or discard high-Cd lines. These findings validate the use of a QTL-based strategy as a highly effective method for improving the efficiency of predictive ability of GS for highly complex traits such as resistance or tolerance to HM accumulation. Identification of both large and minor effect QTNs and/or pleiotropic effects hold potential for flax breeding improvement. Candidate gene functional validation can be performed using methods such as genome editing or targeting induced local lesions in genomes (TILLING).

No description available.

To leverage the extreme parallelism of emerging architectures, so that scientific applications can fulfill their high fidelity and multi-physics potential while sustaining high efficiency relative to the limiting resource, numerical algorithms must be redesigned. Algorithmic redesign is capable of shifting the limiting resource, for example from memory or communication to arithmetic capacity. The benefit of algorithmic redesign expands greatly when introducing a tunable tradeoff between accuracy and resources. Scientific applications from diverse sources rely on dense matrix operations. These operations arise in: Schur complements, integral equations, covariances in spatial statistics, ridge regression, radial basis functions from unstructured meshes, and kernel matrices from machine learning, among others. This thesis demonstrates how to extend the problem sizes that may be treated and to reduce their execution time. Two “universes” of algorithmic innovations have emerged to improve computations by orders of magnitude in capacity and runtime. Each introduces a hierarchy, of rank or precision. Tile Low-Rank approximation replaces blocks of dense operator with those of low rank. Mixed precision approximation, increasingly well supported by contemporary hardware, replaces blocks of high with low precision. Herein, we design new high-performance direct solvers based on the synergism of TLR and mixed precision. Since adapting to data sparsity leads to heterogeneous workloads, we rely on task-based runtime systems to orchestrate the scheduling of fine-grained kernels onto computational resources. We first demonstrate how TLR permits to accelerate acoustic scattering and mesh deformation simulations. Our solvers outperform the state-of-art libraries by up to an order of magnitude. Then, we demonstrate the impact of enabling mixed precision in bioinformatics context. Mixed precision enhances the performance up to three-fold speedup. To facilitate the adoption of task-based runtime systems, we introduce the AL4SAN library to provide a common API for the expression and queueing of tasks across multiple dynamic runtime systems. This library handles a variety of workloads at a low overhead, while increasing user productivity. AL4SAN enables interoperability by switching runtimes at runtime, which permits to achieve a twofold speedup on a task-based generalized symmetric eigenvalue solver.