Genetics of Multiple Sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. Current available treatments can slow down the disease progression in the majority of patients, but can neither stop the progression nor cure the patients. MS is a debilitating neurological disease of young adults and it affects 0.1% of the populations of Northern European descent. The prevalence of MS varies globally and locally, and there are several isolated high-risk populations. One such high-risk population is in the Southern Ostrobothnia region of Finland, where the incidence and prevalence are approximately twice those of the surrounding regions. Both environmental and genetic factors are thought to contribute to disease pathogenesis. Twin, half-sib and adoption studies all point towards underlying genetic factors that predispose to MS. In recent years, genome-wide association studies have revealed over fifty genes that are associated with MS. At the start of this thesis project, only one MS locus, HLA-DRB1, was known, whilst shortly after the start two more loci, IL2RA and IL7R, were reported. The aim of this thesis was to find new associated loci, confirm newly found loci and assess the relevance of these known loci within the Southern Ostrobothnian high-risk isolate, and in the Finnish population overall. The association analyses were performed using genome-wide association analysis methods, haplotype analysis and meta-analysis methods. In the first study, 68 Southern Ostrobothnian cases and 136 identity-by-state matched controls were analyzed in a genome-wide association analysis, where an association signal from the SNP rs744166 in the STAT3 gene was discovered. The association signal was replicated in an international sample set of 4487 MS cases and 9778 controls (OR 1.18, 95% CI 1.12-1.24, p=2.75×10-10). In order to further understand the association signal, a haplotype analysis was performed, revealing that the association signal was on a common haplotype. Further, in a genome-wide homozygosity analysis, excess homozygosity was found in the 68 cases compared to the 136 controls in three genomic loci, 1q42.12, 2q24.3 and 12q24.33. The importance of these loci requires further study. The second study aimed to replicate loci that had previously been observed to associate with MS in an international genome-wide meta-analysis. Three SNPs in three loci, IRF8, TNFRSF1A and CD6, were genotyped in 608 trios, 8439 MS cases, and 9280 controls from 11 populations of European origin, replicating the associations in all three loci. The SNP in IRF8 was strongly associated with MS, while the SNPs in TNTRSF1A and CD6 indicated slightly weaker association. The odds ratios for all the three loci were similarly modest: IRF8 OR 1.11, TNFRSF1A OR 1.12, and CD6 OR 1.11. Since the prevalence and incidence of MS is two-fold in the Southern Ostrobothnian region and there is evidence for founder effect, the aim of the last study was to assess the accumulation of recently identified genome-wide significant MS-associated common risk alleles in the Southern Ostrobothnian isolate MS cases and in familial samples. However, we could not detect accumulation of common variants in the isolate region or in the families compared to general Finnish samples or non-familial samples.Multippeliskleroosi, eli MS-tauti, on krooninen monitekijäinen keskushermoston autoimmuunisairaus, jonka syntyyn vaikuttavat monet ympäristö- ja perintötekijät. Tässä väitöskirjatyössä on etsitty ja tutkittu perintötekijöitä, jotka voivat osaltaan altistaa kantajansa MS-taudille. Tutkimuksissamme havaittiin, että STAT3-geeni on yksi monesta MS taudin riskigeenistä. Lisäksi vahvistimme aiemmin tunnistettujen TNFRSF1A, IRF8 ja CD6 geenien yhteyden MS-tautiriskiin. Näiden geenien uskotaan vaikuttavan elimistön immuunipuolustuksen valkosolujen toimintaan ja kehitykseen. MS-taudissa elimistön oma immuunipuolustus tuhoaa paikallisesti aivojen ja selkäytimen hermosolujen viejähaarakkeita peittävää myeliiniä, ja aiheuttaa samalla hermosolujen viejähaarakkeiden tuhoutumista. Sairauden oirekirjo on laaja, mutta tauti ilmenee usein aaltomaisesti tai tasaisesti etenevänä vammautumisena. Taudin syntysyy ja mekanismi tunnetaan puutteellisesti, eikä tautiin ole löydetty parantavaa tai etenemisen pysäyttävää hoitoa. Tautimekanismin parempi tuntemus onkin perusedellytys parempien hoitomuotojen kehittämiselle MS-taudissa. Viimeaikaiset geneettiset ja solubiologiset tutkimukset ovat tunnistaneet perimässämme useita taudille altistavia geenimuotoja, jotka ovat valottaneet taudin syntyyn vaikuttavia mekanismeja. Vaikka ympäristötekijöillä on merkittävä rooli taudin synnyssä, niitä tunnetaan edelleen vähän. Suomessa noin yksi ihminen tuhannesta sairastaa MS-tautia, mutta taudin esiintyvyys vaihtelee sekä Suomen sisällä, että maailmanlaajuisesti. Etelä-Pohjanmaalla MS-taudin esiintyvyys on kaksinkertainen verrattuna muuhun Suomeen, ja alueen MS-potilaiden perheissä on usein muitakin MS-potilaita. On oletettavaa, että alueelle on kertynyt perinnöllisiä tekijöitä, jotka altistavat MS-taudille ja ovat mahdollisesti harvinaisia muualla maailmassa. Olemme tutkimuksissamme keskittyneet erityisesti Etelä-Pohjanmaan MS-potilaisiin, joiden avulla löysimme yhteyden MS-taudin ja STAT3-geenin tietyn muodon välillä. Löytämämme geenimuodon vaikutus yksittäisenä tekijänä on pieni, kuten muidenkin MS taudille altistavien geenimuotojen. Yhdessä muun tiedeyhteisön tutkimuksen kanssa ne kuitenkin lisäävät ja tarkentavat käsitystämme MS-taudin perusmekanismeista

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes

Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal

Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT) : a study of discordant monozygotic twins with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals. Such comparisons often yield ambiguous conclusions, as alterations could reflect different effects depending on the comparison. Whereas differences found in acutely ill patients could reflect state effects that are due to acute starvation or acute disease-specific factors, they could also reflect underlying traits. Observations in recovered individuals could reflect either an underlying trait or a "scar" due to lasting effects of sustained undernutrition and illness. The co-twin control design (i.e., monozygotic [MZ] twins who are discordant for AN and MZ concordant control twin pairs) affords at least partial disambiguation of these effects. METHODS: Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT) will be the largest and most comprehensive investigation of twins who are discordant for AN to date. CREAT utilizes a co-twin control design that includes endocrinological, neurocognitive, neuroimaging, genomic, and multi-omic approaches coupled with an experimental component that explores the impact of an overnight fast on most measured parameters. DISCUSSION: The multimodal longitudinal twin assessment of the CREAT study will help to disambiguate state, trait, and "scar" effects, and thereby enable a deeper understanding of the contribution of genetics, epigenetics, cognitive functions, brain structure and function, metabolism, endocrinology, microbiology, and immunology to the etiology and maintenance of AN