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Neurodevelopmental disorders on the impulsivity-compulsivity spectrum are chronic disabling conditions with an early onset. High rates of comorbidity have been reported between Tourette syndrome (TS), Tics disorder (Tics), obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) and these disorders share cross-disorder risk, conferred by common variants. In this thesis the focus is on the genetics of human intracranial volume (ICV) and five impulsivity-compulsivity spectrum neurological disorders (Tourette, Tics, OCD, ADHD, and restless legs syndrome (RLS)) with the aim of finding novel sequence variants conferring risk of these behaviours and study their cross disorder risk. The genetics of these disorders is complex. Despite large meta analyses, relatively few sequence variants have been associated with these disorders and perturbed biochemical pathways have not been clearly outlined. Better understanding of their genetic underpinnings may greatly improve and accelerate diagnosis, give insights into disease processes, and point to novel targets for drug therapies. Copy number variations (CNVs) introduce insertion/deletion throughout the genome thereby impacting gene expression through gene dosage effect. A candidate gene study confirms AADAC deletion as a risk factor for TS. Moreover, a group of rare, recurrent CNVs, so called neuropsychiatric CNVs, confer high risk of ADHD. This association highlighted shared genetic risk of ADHD with ASD and schizophrenia. The GWAS meta-analysis of TS didn’t find any significant association while aggregate risk score of common variants confirmed polygenic nature of TS. Through large meta-analyses, more sequence variants conferring risk of diseases of the impulsivity-compulsivity spectrum have been uncovered. Colocalization analyses were used to identify affected genes and Mendelian randomization to search for causal relationships, with a focus on the biological insights these associations are beginning to produce. Variations in ICV can impact brain structure-function relationships. The GWAS meta-analysis of ICV uncovered 64 sequence variants explaining 5.0% of the trait’s variance. Genetic correlation analysis shows positive correlation between ICV and cognitive abilities and neurological traits. Phenome-wide genetic correlation (GC) and causal analyses were used to dissect complex polygenic nature of TS, Tics, ADHD, OCD, and RLS. GC of these five disorders with 1,140 published GWAS studies identified 59 common genetically correlated traits (FDR < 0.05). The hierarchical clustering of 59 correlated traits identified five latent clusters: (1) neuropsychiatric or neurotic disorders, (2) emotional disorders, (3) peripheral and muscular pain (4) obesity / poor lifestyle, and (5) cognition / learning traits. Rare and common variants associate with TS, ADHD, RLS, and ICV. The key question is whether variants, associated with structural changes in the brain, cause neurological disorders through their effect on brain structure or alternatively whether genetic predisposition to certain neurological disorders impacts brain structure or development. Bidirectional MR analyses of 34 correlated disorders compared with ICV revealed that ICV either has a causal effect on a neurodevelopmental disorder (ADHD) as well as on a neurodegenerative disorder (Parkinson’s) or these causal relationships may be driven by traits closely correlated with ICV., Taugaþroskaraskanir á hvatvísis-þráhyggju rófinu eru þrálát og hamlandi einkenni sem koma oft fram snemma á lífsleiðinni. Há tíðni fylgiraskana finnast samhliða Tourette heilkenni (TS), kækjum (Tics), þráhyggju- og áráttu- hegðun (OCD), athyglisbrest með og án ofvirkni röskun (ADHD), og einhverfurófsröskun (ASD) og dæmi eru um að sömu algengu breytileikarnir auka áhættu á mismunandi röskunum. Þessi ritgerð fjallar um erfðafræði rúmmáls heila og fimm taugaþroskaraskana á hvatvísis-þráhyggju rófinu (Tourette, Tics, OCD, ADHD, og fótaóeirð (RLS)) með það að markmiði að finna nýja breytileika sem ávísa áhættu af því að þróa þessar svipgerðir og að rannsaka áhættu á krossröskun. Erfðafræði þessara raskana er flókin. Þrátt fyrir stórar safngreiningar (meta-analysis), hafa tiltölulega fáir breytileikar fundist sem ávísa áhættu á þessum röskunum, né varpað ljósi á þá líffræðilegu ferla sem þar liggja að baki. Betri skilningur á erfðafræðilegri undirstöðu þessara raskana gæti stórbætt og flýtt fyrir greiningu, gefið betri innsýn inn í sjúkdómsferlið og bent á nýjar lyfjameðferðir. Eintakabreytileikar annaðhvort koma fyrir innskotum eða eyða út svæðum í erfðamenginu og hafa þannig áhrif á hversu mikið er tjáð af genum sem eru á þeirra áhrifasvæði. Leit í líklegum genum staðfestir að úrfelling á AADAC geninu er áhættu þáttur fyrir Tourette heilkenni. Þar að auki, höfum við sýnt fram á tengls á milli ákveðinna eintakabreytileika, sem hafa áður verið tengdir við einhverfu og geðklofa, og ADHD. Þessi fylgni varpar ljósi á þá erfðafræðilegu áhættu sem ADHD deilir með einhverfu og geðklofa. Safngreining niðurstaðna úr víðtækri erfðamengisleit skilaði engum erfðabreytileikum sem voru í marktægt hærri tíðni í TS en í viðmiðunarhópi. Þó staðfestir samanlagt arfgerðar-skor fjölgena eðli Tourette heilkennis. Stórar safngreiningar hafa auðkennt nýja breytileika sem ávísa áhættu á röskun á hvatvísis-þráhyggju rófinu. Staðsetning breytileika og aðrar aðferðir hafa verið notaðar til að tengja breytileika við gen og Mendelsku slembivali beitt til að rýna í orsakasamhengi, með fókus á líffræðilega ferla þessi gen taka þátt í. Breytileiki í rúmmáli heilans getur haft áhrif á tengsl á milli uppbyggingu og virkni í heilanum. Stór safngreining niðurstaðna úr víðtækri erfðamengisleit á rúmmáli heilans hefur leitt í ljós 64 breytileika í erfðamenginu sem útskýra um iv 5.0% dreifni svipgerðarinnar. Erfðafylgnigreining (GC) sýnir jákvæða fylgni á milli rúmmáls heilans og vitrænna hæfileika og taugasjúkdóma. Breið svipgerða erfðafylgni greining og orsakagreiningar voru notaðar til að kryfja flókin fjölgena sambönd á milli TS, kækja, ADHD, OCD og RLS. GC þessara fimm raskana á móti 1,140 birtra niðurstaðana úr heilgenóms erfðatengslaleitum, bar kennsl á 59 algeng svipbrigði sem eru sýna marktæka erfðafylgni (FDR < 0.05). Stigveldis þyrpingagreining á þessu 59 svipgerðum leiddi í ljós fimm dulda klasa; (1) taugaþroska- og geðraskanir, (2) tilfinningar raskanir, (3) útlima og vöðva verkir, (4) offita / óheilbrigður lífstíll, (5) vitsmuna / lærdóms svipgerðir. Sjaldgæfir og algengir breytielikar hafa verið tengdir við TS, ADHD, RLS og rúmmál heilans. Lykil spurning er hvort breytileikarnir, sem hafa verið tengdir við breytingar í heila, valdi taugasjókdómum í gegnum áhrifin sem þeir hafa á heilann, eða hvort erfðafræðileg tilhneiging til að þróa taugasjókdóma hefur áhrif á uppbyggingu og þroska heilans. Tvíátta Mendelsk slmbivals greining á 34 svipgerðum, með innbyrgðis fylgni, samanborið við rúmmál heilans gaf til kynna að rúmmál heilans annað hvort hefur áhrif á taugaþroska raskanir (ADHD) og taugasjókdóma (Parkinson’s) eða þá að orsakasamhengið sé stýrt af svipgerðum sem sýna sterka fylgni við rúmmál heilans., Gran support from the Marie Curie Initial Training Networks TS-EUROTRAIN (FP7-PEOPLE [Grant No. GA 316978]), and deCODE Genetics/Amgen, Iceland.

Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid- beta peptide (Aβ) containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Aβ and p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase- inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation,Aβ and p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-α with respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation.