Translating genetic epidemiology to health applications with large-scale biobank data

The field of genetic epidemiology has taken great leaps in the last few decades driven by developments in sequencing technologies, digitalization of health data, evolution of statistical methods, abundance of computational resources, and emergence of large research data infrastructures. This thesis describes three approaches of utilizing novel large data resources and modern methods of genetic epidemiology in understanding human disease, and further outlines general principles behind translation of such findings towards clinical practice. First, we explore how longitudinal secondary health data together with data-driven statistical learning methods can be utilized to develop health metrics for public health surveillance. We construct a novel healthy aging score from 21 years of medication purchase and mortality data, validate it in two external cohorts, and show that the new score complements Charlson Comorbidity Index, associates with genomic risks of late-onset diseases, and has a reasonable accuracy in predicting all-cause mortality out-of-sample. Second, we investigate how polygenic risk score of migraine, a computational biomarker of genome-wide common variant burden, relates to the official ICHD-3 migraine diagnosis criteria in a deeply phenotyped large migraine database. We find that the disease complexity correlates consistently with increasing polygenic risk and then rank diagnostic criteria by strength of their association. Our results bring clinical depth to the opaque basic research biomarker that combines the effect of numerous genetic variants into a single value. Third, we use multiple large data resources to identify a Finnish-enriched missense risk variant for idiopathic pulmonary fibrosis, to explore its pleiotropic link to common cancers, and to inform on its possible biological mechanisms. Results provide a hypothesis of a link related to cellular senescence and mitotic checkpoint signaling, a potential target for further therapeutic investigations. This study exemplifies the many benefits of novel genomic data resources on identifying and exploring novel potential therapeutic targets. All results contribute to their respective research domains and together demonstrate different ways in which large research data infrastructures and methods of modern genetic epidemiology can provide novel insights and potential new applications to health care. Bringing these visions to reality would require further wide translational efforts of multidisciplinary nature.Geneettisen epidemiologian tutkimus on edennyt suurin harppauksin viime vuosikymmeninä. Uuden polven sekvensointiteknologiat, terveystiedon digitalisoituminen, tilastollisten metodien kehitys, laskentakapasiteetin lähes rajaton saatavuus ja suurten tutkimusinfrastruktuurien synty ovat olleet tämän kehityksen kulmakiviä. Tässä väitöskirjassa tarkastellaan kolmea tapaa hyödyntää uusia suuria data-aineistoja ja moderneja menetelmiä sairauksien ymmärtämiseksi sekä kuvataan yleisiä periaatteita, joilla löydöksiä voitaisiin viedä eteenpäin kohti kliinistä hyödyntämistä. Ensin tutkimme, kuinka terveydenhuollossa kertynyttä tietoa voitaisiin toisiohyödyntää oppivien tilastollisten menetelmien avulla kansanterveydellisten seurantatyökalujen kehittämiseen. Tutkimuksessa yhdistetään lääkeosto- ja kuolleisuustietoa 21 vuoden ajalta uudenlaiseksi terveellisen ikääntymisen mittariksi. Mittari validoidaan kahdessa ulkopuolisessa tutkimusaineistossa ja osoitetaan, että se täydentää perinteistä riskityökalua (Charlson Comorbidity Index), assosioituu myöhäisiän sairauksien geneettiseen riskiin ja ennustaa kuolleisuutta otoksen ulkopuolella. Toiseksi tarkastelemme, kuinka migreenin geneettinen riskipisteytys, joka kuvaa yleisten varianttien rasitetta genominlaajuisesti, heijastuu vakiintuneeseen ICHD-3-diagnoosikriteeristöön laajassa ja yksityiskohtaisessa migreeniaineistossa. Osoitamme, että migreenin oirekuvan voimakkuus korreloi korkeamman polygeenisen riskin kanssa ja kuvaamme kuinka diagnoosikriteerit keskenään järjestyvät suhteessa kasvavaan riskiin. Tulokset tuovat kliinisesti syvempää tartuntapintaa uuteen perustutkimukselliseen biomarkkeriin, joka yhdistää lukemattomien geneettisten tekijöiden yhteisvaikutuksen yhteen numeriseen arvoon. Kolmannessa osatyössä tunnistetaan Suomeen rikastunut idiopaattiselle keuhkofibroosille altistava missense-variantti, kuvataan sen pleiotropiaa yleisiin syöpiin sekä etsitään selityksiä ilmiön mahdolliselle mekanismille laajojen data-aineistojen avulla. Tutkimuksessa luodaan hypoteesi geenivariantin yhteydestä solusenesenssiin ja mitoottiseen tarkastuspisteeseen, jotka voisivat toimia mahdollisina tulevaisuuden terapioiden jatkotutkimuksen lähtökohtina. Työ kuvaa monelta kantilta niitä hyötyjä, joita uudenlaiset laajat tietoaineistot voivat tuoda lääkeaihioiden etsimiseen ja terapioiden monisyiseen alkuvaiheen tutkimiseen. Kukin osatöistä tuo uutta tietoa omalle tutkimusalueelleen ja tulokset yhdessä havainnollistavat, kuinka suuret tutkimusinfrastruktuurit laajoine data-aineistoineen sekä moderni geneettinen epidemiologia voivat luoda uusia näkökulmia ja potentiaalisia tulevaisuuden sovelluksia terveydenhuoltoon. Näiden visioiden jatkotranslaatio ja tuominen käytäntöön vaatisi laajaa monitieteellistä jatkotutkimusta

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Objective: Identifying common genetic variants that confer genetic risk for cluster headache. Methods: We conducted a case–control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10−8), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33–1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203–216.Peer reviewe

Migreenin geneettinen tausta on monitekijäinen

Vertaisarvioitu.Migreeni on yleinen neurovaskulaarinen aivosairaus, jolla on vahva geneettinen tausta. Migreenin molekyyligeneettiset tutkimukset 1990-luvulla kohdistuivat harvinaiseen hemiplegiseen migreeniin, joka osoittautui ionikanavataudiksi. Yleisten migreenimuotojen geneettinen tausta alkoi hahmottua 2010-luvulla genominlaajuisten assosiaatiotutkimusten (GWAS) avulla. Tutkimukset ovat paljastaneet kymmeniä yleisiä, vaikutukseltaan vähäisiä migreenin geneettisiä riskivariantteja, erityisesti vaskulaarisissa kudoksissa ilmenevistä geeneistä. On selvinnyt, että aurallisen, aurattoman ja hemiplegisen migreenin riskivariantit ovat osittain samoja. Yleisten riskivarianttien yhteisvaikutus taas selittää migreenin kertymistä perheisiin. Mielenkiintoista on myös se, että migreenillä on yhteisiä geneettisiä riskitekijöitä psyykkisten sairauksien, erityisesti ADHD:n, vakavan masennuksen ja Touretten oireyhtymän kanssa. Riskivarianttien todellinen merkitys migreenin patofysiologiaan selviää vasta toiminnallisten tutkimusten avulla.Peer reviewe

A data-driven medication score predicts 10-year mortality among aging adults

Health differences among the elderly and the role of medical treatments are topical issues in aging societies. We demonstrate the use of modern statistical learning methods to develop a data-driven health measure based on 21 years of pharmacy purchase and mortality data of 12,047 aging individuals. The resulting score was validated with 33,616 individuals from two fully independent datasets and it is strongly associated with all-cause mortality (HR 1.18 per point increase in score; 95% CI 1.14-1.22; p=2.25e-16). When combined with Charlson comorbidity index, individuals with elevated medication score and comorbidity index had over six times higher risk (HR 6.30; 95% CI 3.84-10.3; AUC=0.802) compared to individuals with a protective score profile. Alone, the medication score performs similarly to the Charlson comorbidity index and is associated with polygenic risk for coronary heart disease and type 2 diabetes.Peer reviewe

NCOR2 is a novel candidate gene for migraine-epilepsy phenotype

Hypothesis To identify genetic factors predisposing to migraine-epilepsy phenotype utilizing a multi-generational family with known linkage to chr12q24.2-q24.3. Methods We used single nucleotide polymorphism (SNP) genotyping and next-generation sequencing technologies to perform linkage, haplotype, and variant analyses in an extended Finnish migraine-epilepsy family (n = 120). In addition, we used a large genome-wide association study (GWAS) dataset of migraine and two biobank studies, UK Biobank and FinnGen, to test whether variants within the susceptibility region associate with migraine or epilepsy related phenotypes in a population setting. Results The family showed the highest evidence of linkage (LOD 3.42) between rs7966411 and epilepsy. The haplotype shared among 12 out of 13 epilepsy patients in the family covers almost the entire NCOR2 and co-localizes with one of the risk loci of the recent GWAS on migraine. The haplotype harbors nine low-frequency variants with potential regulatory functions. Three of them, in addition to two common variants, show nominal associations with neurological disorders in either UK Biobank or FinnGen. Conclusion We provide several independent lines of evidence supporting association between migraine-epilepsy phenotype and NCOR2. Our study suggests that NCOR2 may have a role in both migraine and epilepsy and thus would provide evidence for shared pathophysiology underlying these two diseases.Peer reviewe

Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families

Background Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. Methods We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. Results Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. Conclusions The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.Peer reviewe

Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

Publisher Copyright: © 2022 The Author(s)The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor—the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.Peer reviewe

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine : A clinical and genetic study in Finnish migraine families

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.Peer reviewe

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine

Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics

The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor—the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.publishedVersionPeer reviewe