Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

Most known genetic causes of severe childhood developmental disorders are rare, deleterious, protein-coding changes that cause Mendelian disorders. Children with these disorders typically show early-onset impairment in growth, learning and adaptive behaviours. Linkage and whole exome sequencing studies on these patients have previously focused on identifying diagnostic rare variants that are solely responsible for the patient’s phenotype. In this thesis, I investigate whether common, inherited genetic variation also plays a modifying role in severe, presumably Mendelian neurodevelopmental disorders. In addition, I study the effects of common variants on the cognitive functioning of healthy individuals, who carry rare deleterious variants in genes that are intolerant to such variants in the general population. To test whether common variants contribute to neurodevelopmental disorders that are expected to be almost entirely monogenic, I conduct a genome-wide association study (GWAS) in nearly 7,000 patients from the Deciphering Developmental Disorders (DDD) Study and ancestry-matched controls. I show that common genetic variants explain almost 8% of variation in risk for these severe disorders. I also find genetic overlap between our study and GWAS for other cognitive and neuropsychiatric traits. This suggests that common variants individually have a small effect on brain development and functioning, influencing both risk for common diseases in the population and risk for severe disorders that affect only a small number of individuals. This polygenic burden in the DDD is also not confined to only patients who do not have diagnostic rare variants. Altogether, these results may have important implications for understanding variable clinical presentation of neurodevelopmental disorders and searching for secondary genetic modifiers. Finally, I assess the interplay between common and rare variants on the cognitive functioning of seemingly healthy individuals. Using data from the INTERVAL Study, I test whether common variants are protective of the deleterious rare variants in these individuals. Whilst these analyses are potentially currently underpowered, with additional samples in the future, we may be able to shed more light on expressivity and penetrance of deleterious variants in the general population.Wellcome Trus

The Role of Trees in the Cult of Attis : Holy Pine in Myths, Rites and Art

Maisterintutkielmassani tutkin, mitä puut voivat paljastaa meille antiikin uskontoihin lukeutuvasta Attiksen kultista, jossa niiden läsnäolo näkyy niin myyteissä, taiteessa kuin rituaaleissa. Erityisesti Attikseen yhdistettiin pinja, Välimerellä kasvava havupuu, ja työssäni selvitän, miksi juuri pinja valikoitui Attiksen rinnalle ja mitä kyseinen puu ja siihen liittyvä symboliikka kertoo Attiksesta jumalana sekä hänen kultistaan. Attiksen ja hänen kulttinsa lisäksi perehdyn itse pinjaan, ja osoitan, että se ei ollut pelkkä symboli ja muistomerkki vaan pyhä puu, itsessään arvokas ja merkityksekäs. Tarkastelen työssäni myös Attiksen kultin kehitystä keisarikaudelta myöhäisantiikkiin ja käyn läpi sen yleisimpiä piirteitä. Attis kuvattiin useimmiten fryygialaisena miehenä, jonka myyttinen alkuperä kietoutui yhteen jumalatar Kybelen kanssa. Ajoittain kulttitasolla on vaikea erottaa, miten erilaiset rituaalit ja käytänteet näiden kahden välille asettuvat ja kumpaa erilaisissa riiteissä oikeastaan kunnioitettiin. Toisaalta tarkan jaon tekeminen ei ole tarpeellista, sillä he kuuluivat erottamattomasti yhteen. Tästä huolimatta työni keskittyy Attikseen ja hänen rooliinsa kultissa. Kybele kulkee kuitenkin aina rinnalla tarkastelussani. Lähteinäni toimivat antiikin kirjoittajien erilaiset versiot Kybelen ja Attiksen myytistä sekä arkeologinen kuva-aineisto, joita olen tulkinnut historiantutkimuksen metodein lähiluvun ja hermeneuttisen analyysin kautta. Alueellisesti aiheeni kattaa Rooman valtakunnan koko laajuudessaan keskittyen Roomaan ja sen lähialueisiin sekä Kreikkaan ja Galliaan. Ajallisesti tarkastelen roomalaisaikaa 100-luvulta ennen ajanlaskun alkua alkaen, mutta pääpaino työssäni on ajanlaskun alusta myöhäisantiikkiin. Lähdeaineiston valossa Attiksen ja pinjan yhteys näyttäytyy kiistattomana. Myytit kuvaavat hänen syntymäänsä puun hedelmästä ja hänen kuolemaansa pinjapuun juurella. Kuvataiteessa pinja oli yksi Attiksen tunnistettavimmista attribuuteista, ja hänen maaliskuun juhlapäiviensä kohokohta oli arbor intrat rituaali, jossa Attiksen identiteetin omaksunut pinjapuun runko kannettiin Kybelen temppeliin. Pinjapuun ja Attiksen yhteys kertoo heidän jakamastaan identiteetistä, joka kiteytyy ikivihreyteen. Lisäksi pinjaan liittyvät symbolit paljastavat keskeisiä ideoita Attiksen kultin taustalta: hedelmällisyyden, syklisyyden ja ikuisen elämän. Roomassa ei ollut vain yhtä tapaa tai syytä pitää puuta pyhänä, vaan hyvin monenlaiset tekijät saattoivat olla sen erityislaatuisen aseman takana. Pinjan pyhyyden puolesta puhuvat jo itsessään sen läheinen yhteys Attikseen, mutta myös Ovidiuksen kuvailema metamorfoosi, jossa Attis muuttuu itse pinjaksi. Puun rooli osana rituaaleja vahvisti sen pyhää statusta, minkä temppeliin kanto sinetöi, sillä temppelien sisäpuoli nähtiin jumalten alueena

Cortical Sequence of Word Perception in Beginning Readers

Efficient analysis of written words in normal reading is likely to reflect use of neural circuits formed by experience during childhood rather than an innate process. We investigated the cortical sequence of word perception in first-graders (7–8 years old), with special emphasis on occipitotemporal cortex in which, in adults, letter-string-sensitive responses are detected at 150 ms after stimulus. To identify neural activation that is sensitive to either the amount of basic visual features or specifically to letter strings, we recorded whole-head magnetoencephalography responses to words embedded in three different levels of noise and to symbol strings. As was shown previously in adults, activation reflecting stimulus nonspecific visual feature analysis was localized to occipital cortex in children. It was followed by letter-string-sensitive activation in the left occipitotemporal cortex and, subsequently, in the temporal cortex. These processing stages were correlated in timing and activation strength. Compared with adults, however, the timing of activation was clearly delayed in children, and the delay was progressively increased from occipital to occipitotemporal and further to temporal areas. This finding is likely to reflect increasing immaturity of the underlying neural generators when advancing from low-level visual analysis to higher-order areas involved in written word perception. When a salient occipitotemporal letter-string-sensitive activation was detected (10 of 18 children), its strength was correlated with phonological skills, in line with the known relevance of phonological awareness in reading acquisition.Peer reviewe

The role of legumes in bioenergy poduction

We are investigating the role of legumes as components of bioenergy production. Two separate experiments, one with annual species and other with perennials, were established at Viikki in 2007. Selected grasses, legumes (or nitrogen fertilizer) and additional species were sown singly or in blends of two or three species

Young, metal-enriched cores in early-type dwarf galaxies in the Virgo cluster based on colour gradients

Early-type dwarf galaxies are not simply featureless, old objects, but were found to be much more diverse, hosting substructures and a variety of stellar population properties. To explore the stellar content of faint early-type galaxies, and to investigate in particular those with recent central star formation, we study colours and colour gradients within one effective radius in optical (g-r) and near-infrared (i-H) bands for 120 Virgo cluster early types with -19 mag < $M_{r}$ < -16 mag. Twelve galaxies turn out to have blue cores, when defined as g-r colour gradients larger than 0.10 mag/$R_{\rm eff}$, which represents the positive tail of the gradient distribution. For these galaxies, we find that they have the strongest age gradients, and that even outside the blue core, their mean stellar population is younger than the mean of ordinary faint early types. The metallicity gradients of these blue-cored early-type dwarf galaxies are, however, in the range of most normal faint early types, which we find to have non-zero gradients with higher central metallicity. The blue central regions are consistent with star formation activity within the last few 100 Myr. We discuss that these galaxies could be explained by environmental quenching of star formation in the outer galaxy regions, while the inner star formation activity has continued

Stirring the Construction Project Management with Co-creation and Continuous Improvement

AbstractGathering information that is capable to explain customers’ needs is usually seen as a quite straightforward part of the traditional construction process: a customer should be able to tell all relevant needs in the first stage so that a building could be designed and built according to the gained information. But the process is lacking of service abilities if a customer wants to modify the given information due to a change in circumstances, albeit such a change is easily caused due turbulent economic situations and long spans in real-estate development projects. Hence the customer perspective regarding the construction management (CM) process should be accommodated better. In this paper, the case studies of the four premises improvement projects are reported upon, where the CM process was altered to include and apply the concepts of continuous improvement and co-creation. The process documentation covered the impacts of the case project on the usability of the premises, the indoor climate conditions (carbon dioxide and temperature) metering, the time lapse cameras and the on-line user feedback system. The documentation consists of the minutes of the meetings, the financial reporting and the time tables.Both the processes and the results of the projects are analysed. Based on the key findings, some suggestions are put forth upon how to improve the CM process to better serve customer interests and quality improvement in the future

Word Reading Skills and Externalizing and Internalizing Problems from Grade 1 to Grade 2 - Developmental Trajectories and Bullying Involvement in Grade 3

School bullying is associated with externalizing and internalizing problems, but little is known about whether reading difficulties also play a part. We asked how, in Grades 1 and 2, word reading skills and externalizing/internalizing problems predict the degree to which students are involved in bullying in Grade 3. Using a sample of 480 Finnish children (M age = 7 years 2 months at the beginning of the study), developmental profiles were identified using mixture modeling based on reading skills, as well as externalizing and internalizing problems. In Grade 3, one fifth of the students were involved in bullying as victims, bullies, or bully/victims. Poor readers with externalizing/internalizing problems were most involved as bullies and bully/victims but not as victims. Average readers with externalizing/internalizing problems were also involved in bullying, whereas students with only reading difficulties were not. Skilled readers displayed little externalizing/internalizing problems and were not involved in bullying.<br /

Longitudinal associations between poor reading skills, bullying and victimization across the transition from elementary to middle school

Students with poor reading skills and reading difficulties (RDs) are at elevated risk for bullying involvement in elementary school, but it is not known whether they are at risk also later in adolescence. This study investigated the longitudinal interplay between reading skills (fluency and comprehension), victimization, and bullying across the transition from elementary to middle school, controlling for externalizing and internalizing problems. The sample consists of 1,824 students (47.3% girls, T1 mean age was 12 years 9 months) from 150 Grade 6 classrooms, whose reading fluency and comprehension, self-reported victimization and bullying, and self-reported externalizing and internalizing problems were measured in Grades 6, 7, and 9. Two cross-lagged panel models with three time-points were fitted to the data separately for reading fluency and comprehension. The results indicated that poorer fluency and comprehension skills in Grade 6 predicted bullying perpetration in Grade 7, and poorer fluency and comprehension skills in Grade 7 predicted bullying perpetration in Grade 9. Neither fluency nor comprehension were longitudinally associated with victimization. The effects of reading skills on bullying perpetration were relatively small and externalizing problems increased the risk for bullying others more than poor reading skills did. However, it is important that those who struggle with reading get academic support in school throughout their school years, and social support when needed.</p