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Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1 , and another in CFAP52 (also known as WDR16 ). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

Left–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits. Genes associated with brain asymmetry are involved with the internal skeletons of cells, and are especially active in the embryo. Some of these genes are associated with handedness and risk for psychiatric disorders.

Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

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 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, hand preference 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. 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.

In this work we endeavor to further understand the genetic architecture of the cerebellum by examining the genetic underpinnings of the different cerebellar lob(ul)es, identifying their genetic relation to cortical and subcortical regions, as well as to psychiatric disorders, as well as traces of their evolutionary trajectories. We confirm the moderate heritability of cerebellar volumes, and reveal genetic clustering and variability across their different substructures, which warranted a detailed analysis using this higher structural resolution. We replicated known genetic correlations with several subcortical volumes, and report new cortico-cerebellar genetic correlations, including negative genetic correlations between anterior cerebellar lobules and cingulate, and positive ones between lateral Crus I and lobule VI with cortical measures in the fusiform region. Heritability partitioning for evolutionary annotations highlighted that the vermis of Crus II has depleted heritability in genomic regions of “archaic introgression deserts”, but no enrichment/depletion of heritability in any other cerebellar regions. Taken together, these findings reveal novel insights into the genetic underpinnings of the different cerebellar lobules.

Reading is an evolutionarily recent development that recruits and tunes brain circuitry connecting primary- and language-processing regions. We investigated whether metrics of the brain’s physical structure correlate with reading performance and whether genetic variants affect this relationship. To this aim, we used the Adolescent Brain Cognitive Development dataset ( n  = 9,013) of 9–10-year-olds and focused on 150 measures of cortical surface area (CSA) and thickness. Our results reveal that reading performance is associated with nine measures of brain structure including relevant regions of the reading network. Furthermore, we show that this relationship is partially mediated by genetic factors for two of these measures: the CSA of the entire left hemisphere and, specifically, of the left superior temporal gyrus CSA. These effects emphasize the complex and subtle interplay between genes, brain and reading, which is a partly heritable polygenic skill that relies on a distributed network. Reading performance is associated with nine measures of brain structure in the left hemisphere, including regions of the reading network. This relationship is partially mediated by genetic factors for two surface area measures: total area and superior temporal gyrus.

Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

Language is a unique trait of the human species, of which the genetic architecture remains largely unknown. Through language disorders studies, many candidate genes were identified. However, such complex and multifactorial trait is unlikely to be driven by only few genes and case-control studies, suffering from a lack of power, struggle to uncover significant variants. In parallel, neuroimaging has significantly contributed to the understanding of structural and functional aspects of language in the human brain and the recent availability of large scale cohorts like UK Biobank have made possible to study language via image-derived endophenotypes in the general population. Because of its strong relationship with task-based fMRI (tbfMRI) activations and its easiness of acquisition, resting-state functional MRI (rsfMRI) have been more popularised, making it a good surrogate of functional neuronal processes. Taking advantage of such a synergistic system by aggregating effects across spatially distributed traits, we performed a multivariate genome-wide association study (mvGWAS) between genetic variations and resting-state functional connectivity (FC) of classical brain language areas in the inferior frontal (pars opercularis, triangularis and orbitalis), temporal and inferior parietal lobes (angular and supramarginal gyri), in 32,186 participants from UK Biobank. Twenty genomic loci were found associated with language FCs, out of which three were replicated in an independent replication sample. A locus in 3p11.1, regulating EPHA3 gene expression, is found associated with FCs of the semantic component of the language network, while a locus in 15q14, regulating THBS1 gene expression is found associated with FCs of the perceptual-motor language processing, bringing novel insights into the neurobiology of language.

Purpose: A phonological deficit is thought to affect most individuals with developmental dyslexia. The present study addresses whether the phonological deficit is caused by difficulties with perceptual learning of fine acoustic details. Method: A demanding test of nonverbal auditory memory, \"noise learning,\" was administered to both adults with dyslexia and control adult participants. On each trial, listeners had to decide whether a stimulus was a 1-s noise token or 2 abutting presentations of the same 0.5-s noise token (repeated noise). Without the listener's knowledge, the exact same noise tokens were presented over many trials. An improved ability to perform the task for such \"reference\" noises reflects learning of their acoustic details. Results: Listeners with dyslexia did not differ from controls in any aspect of the task, qualitatively or quantitatively. They required the same amount of training to achieve discrimination of repeated from nonrepeated noises, and they learned the reference noises as often and as rapidly as the control group. However, they did show all the hallmarks of dyslexia, including a well-characterized phonological deficit. Conclusion: The data did not support the hypothesis that deficits in basic auditory processing or nonverbal learning and memory are the cause of the phonological deficit in dyslexia.

Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development.