Biology subjects

Paschou, P.

Publications and source records attributed to Paschou, P..

3 recordsLinked to original sources

bioRxiv2018

Concordance Of Genetic Variation That Increases Risk For Tourette Syndrome And That Influences Its Underlying Neurocircuitry

BACKGROUNDThere have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variations that increase risk for TS - and its main symptom dimensions - influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS.\n\nMETHODSWe obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4,644 cases and 8,695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP Effect Concordance Analysis (SECA) was used to examine genetic pleiotropy - the same SNP affecting two traits - and concordance - the agreement in SNP effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage Disequilibrium Score Regression (LDSR) was used as validation of SECA.\n\nRESULTSSECA revealed significant pleiotropy between TS and putaminal (p=2x10-4) and caudal (p=4x10-4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p=1x10-3). LDSR lent additional support for the association between TS and thalamic volume (p=5.85x10-2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamic volume (p=1x10-3), as well as concordance between symmetry behaviour and greater putaminal volume (p=7x10-4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p<8x10-7) when conditioning on intracranial (rs2708146, q=0.046; and rs72853320, q=0.035 and hippocampal (rs1922786, q=0.001 volumes respectively.\n\nCONCLUSIONThese data indicate concordance for genetic variations involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

genomics↗

bioRxiv2017

Dissecting Population Substructure in India via Correlation Optimization of Genetics and Geodemographics

India represents an intricate tapestry of population substructure shaped by geography, language, culture and social stratification. While geography closely correlates with genetic structure in other parts of the world, the strict endogamy imposed by the Indian caste system and the large number of spoken languages add further levels of complexity to understand Indian population structure. To date, no study has attempted to model and evaluate how these factors have interacted to shape the patterns of genetic diversity within India. We merged all publicly available data from the Indian subcontinent into a data set of 891 individuals from 90 well-defined groups. Bringing together geography, genetics and demographic factors, we developed COGG (Correlation Optimization of Genetics and Geodemographics) to build a model that explains the observed population genetic substructure. We show that shared language along with social structure have been the most powerful forces in creating paths of gene flow in the subcontinent. Furthermore, we discover the ethnic groups that best capture the diverse genetic substructure highlighted by COGG. Integrating data from India with a data set of additional 1,323 individuals from 50 populations we find that Europeans show shared genetic drift with the Indo-European and Dravidian speakers of India, whereas the East Asians have the maximum shared genetic drift with Tibeto-Burman speaking tribal groups.

genomics↗

bioRxiv2017

TECPR2 a positive regulator of autophagy is implicated in healthy brain ageing

Understanding the healthy brain aging process is key to uncovering the mechanisms leading to pathological age-related neurodegeneration, including progression to Alzheimers disease (AD). Here, we report the first deep whole genome sequencing study aiming to identify variants that are associated specifically to healthy brain aging defined on both clinical and neuropathological level, thus tacking the issue of pathological heterogeneity that often underlies a clinical AD diagnosis. We studied samples from the VITA brain bank and followed an extreme phenotypic ends study design comparing neuropathologically \"healthy\" aging individuals above 80 years of age with pure AD patients of the same age. Focusing on the extreme ends of the phenotypic distribution, and potentially functional variants, we discover a single variant (rs10149146) carried by 53.6% of the \"healthy\" brain elderly individuals in our study (15/28 individuals) and none of the 12 AD cases. This variant lies on the autophagy and cell cycle associated TECPR2 gene. Autophagy dysfunction has been previously implicated in multiple progressive neurodegenerative diseases. An additional non-synonymous variant on the CINP gene (encoding a cell-cycle checkpoint protein) is also found in 46% of healthy controls and absent from all the AD cases. TECPR2 and CINP appear to be \"partner\" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Our study is the first to support the hypothesis that a TECPR2 non-synonymous variant carries a significant neuroprotective effect pointing to key molecules for the involvement of autophagy and cell cycle control in protection from neurodegeneration.

genomics↗