Biology subjects

Francks, C.

Publications and source records attributed to Francks, C..

7 recordsLinked to original sources

bioRxiv2018

The molecular genetics of hand preference revisited

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N=331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence implicating any specific candidate variants previously reported. We also found no evidence that genes involved in visceral laterality play a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Within the UK Biobank itself, a significant association implicates the gene MAP2 in handedness.

genetics↗

bioRxiv2018

Gene Expression Correlates of the Cortical Network Underlying Sentence Processing

A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brains infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.

neuroscience↗

bioRxiv2018

The genetics of situs inversus totalis without primary ciliary dyskinesia

Situs inversus totalis (SIT), a complete left-right mirror reversal of the visceral organs, is usually described as a recessive disorder. SIT can occur with Primary Ciliary Dyskinesia (PCD). However, most people with SIT do not have PCD, and the etiology of their condition remains poorly studied. Those without PCD may have an elevated rate of left-handedness, implying developmental mechanisms linking brain and body laterality. We sequenced the genomes of 15 people with SIT, of which six had PCD, and 15 controls. The SIT subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SIT cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SIT cases. One non-PCD SIT case had a recessive mutation in PKD1L1, which has previously been linked to SIT without PCD. However, six of the nine non-PCD SIT cases, including most of the left-handers in this dataset, had no obvious candidate genes or significant pathways affected by the mutations that they carried. While we cannot exclude a monogenic basis, more complex genetic models must also be considered, as well as environmental influences or random effects in early development.

genetics↗

bioRxiv2018

Genome Wide Association Scan identifies new variants associated with a cognitive predictor of dyslexia.

Developmental dyslexia (DD) is one of the most prevalent learning disorders among children and is characterized by deficits in different cognitive skills, including reading, spelling, short term memory and others. To help unravel the genetic basis of these skills, we conducted a Genome Wide Association Study (GWAS), including nine cohorts of reading-impaired and typically developing children of European ancestry, recruited across different countries (N=2,562-3,468).\n\nWe observed a genome-wide significant effect (p<1x10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2 within MIR924HG (micro-RNA 924 host gene; p = 4.73x10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; p = 2.25 x10-8). RAN represents one of the best universal predictors of reading fluency across orthographies and linkage to RAN has been previously reported within CELF4 (18q12.2), a gene highly expressed in the fetal brain which is co-expressed with NKAIN3 and predicted to be a target of MIR924. These findings suggest new candidate DD susceptibility genes and provide insights into the genetics and neurobiology of dyslexia.

genomics↗

bioRxiv2018

Early life factors influencing hand preference in the UK biobank cohort

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large, general population cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, handedness was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Maternal smoking showed no association with handedness. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference. Therefore other, unknown effects must be involved, including possible environmental factors, and/or random developmental variation with respect to the left-right formation of the embryonic brain.\n\nSignificance statementLeft-right laterality is an important aspect of human brain organization which is set up early in development. Left-handedness is an overt and relatively prevalent form of atypical brain laterality. Various, often related, early life factors have been previously studied in relation to handedness, but often in small samples, or samples with biased selection schemes. Here we have performed the largest ever study of left-handedness in relation to early life factors. Left-handedness was very weakly heritable and there were significant effects of various factors such as birthweight, which remained significant after controlling for all others. However, considered all together, early life factors still had poor predictive power for the handedness of any given individual. Very early developmental perturbations, caused by environmental or chance effects in embryonic development, are therefore likely to cause left-handedness.

developmental biology↗

bioRxiv2018

Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Left-right laterality is an important aspect of human brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and fetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.

genomics↗

bioRxiv2017

Multivariate genome-wide association study of rapid automatized naming and rapid alternating stimulus in Hispanic and African American youth.

Reading disability is a complex neurodevelopmental disorder that is characterized by difficulties in reading despite educational opportunity and normal intelligence. Performance on rapid automatized naming (RAN) and rapid alternating stimulus (RAS) tests gives a reliable predictor of reading outcome. These tasks involve the integration of different neural and cognitive processes required in a mature reading brain. Most studies examining the genetic factors that contribute to RAN and RAS performance have focused on pedigree-based analyses in samples of European descent, with limited representation of groups with Hispanic or African ancestry. In the present study, we conducted a multivariate genome-wide association analysis to identify shared genetic factors that contribute to performance across RAN Objects, RAN Letters, and RAS Letters/Numbers in a sample of Hispanic and African American youth (n=1,331). We then tested whether these factors also contribute to variance in reading fluency and word reading. Genome-wide significant, pleiotropic, effects across RAN Objects, RAN Letters, and RAS Letters/Numbers were observed for SNPs located on chromosome 10q23.31 (rs1555839, multivariate association, p=2.23 x 10-8), which also showed significant association with reading fluency and word reading performance (p <0.001). Bioinformatic analysis of this region using epigenetic data from the NIH Roadmap Epigenomics Mapping Consortium indicates active transcription of the gene RNLS in the brain. Neuroimaging genetic analysis of fourteen cortical regions in an independent sample of typically developing children across multiple ethnicities (n=690) showed that rs1555839 was associated with variation in volume of the right inferior parietal cortex--a region of the brain that processes numerical information and has been implicated in reading disability. This study provides support for a novel locus on chromosome 10q23.31 associated with RAN, RAS, and reading-related performance.\n\nAUTHOR SUMMARYReading disability has a strong genetic component that is explained by multiple genes and genetic factors. The complex genetic architecture along with diverse cognitive impairments associated with reading disability, poses challenges in identifying novel genes and variants that confer risk. One method to begin parsing genetic and neurobiological mechanisms that contribute to reading disability is to take advantage of the high correlation among reading-related cognitive traits like rapid automatized naming (RAN) and rapid alternating stimulus (RAS) to identify shared genetic factors that contribute to common biological mechanisms. In the present study, we used a multivariate genome-wide analysis approach that identified a region of chromosome 10q23.31 associated with variation in RAN Objects, RAN Letters, and RAS Letters/Numbers performance in a sample of 1,331 Hispanic and African American youth in the Genes, Reading, and Dyslexia (GRaD) Study. Genetic variants in this region were also associated with reading fluency in GRaD, and differences in brain structures implicated in reading disability in a separate sample of 690 children. The gene, RNLS, is located within the implicated region of chromosome 10q23.31 and plays a role in breaking down a class of chemical messengers known to affect attention, learning, and memory in the brain. These findings provide a basis to inform our understanding of the biological basis of reading disability.

genetics↗