Using neuroimaging genomics to investigate the evolution of human brain structure

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past

SETBP1 variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder

Germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders. Heterozygous missense variants at a hotspot encoding a canonical degron lead to SETBP1 accumulation and Schinzel-Giedion syndrome (SGS), a rare severe developmental disorder involving multisystem malformations. Heterozygous loss-of-function variants result in SETBP1 haploinsufficiency disorder which is phenotypically much milder than SGS. Following an initial description of four individuals with atypical SGS carrying heterozygous missense variants adjacent to the degron, a few individual cases of variants outside the degron were reported. Due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of the roles of the gene in brain development, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive, imposing challenges for diagnosis and patient care. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron (n=18, including one in-frame deletion). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1 haploinsufficiency disorder, and primarily characterised by intellectual disability, epilepsy, speech and motor impairment. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding and transcription. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care and aetiology of SETBP1-related disorders

Discovery of 42 genome-wide significant loci associated with dyslexia

Funding: EE, GA, BM, BSP, CF and SEF are supported by the Max Planck Society (Germany). The Chinese Reading Study was supported by grants from the National Natural Science Foundation of China Youth Project (Grant No. 61807023), the Youth Fund for Humanities and Social Sciences Research of the Ministry of Education (Grant No. 19YJC190023 and 17XJC190010), and the Natural Science Basic Research Plan in Shaanxi Province of China (Grant No. 2021JQ-309). SP is funded by the Royal Society.Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.Publisher PDFPeer reviewe

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, in samples of 13,633 to 33,959 participants aged 5-26 years. We identified genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP-heritability, accounting for 13-26% of trait variability. Genomic structural equation modelling revealed a shared genetic factor explaining most variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain, and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of uniquely human traits

SILICONE OIL BARRIER SUTURES IN APHAKIC EYES WITH IRIS DEFECTS.

PURPOSE: To evaluate the efficacy and safety of silicone oil barrier sutures in aphakic eyes with iris defects. METHODS: Sixteen aphakic and iris-defective eyes of 16 patients who underwent a pars plana vitrectomy procedure with silicone oil tamponade because of retinal detachment were included in this retrospective study. Silicone oil barrier sutures were placed as a grid pattern within the plane of the previous iris after vitrectomy and before silicone oil injection. RESULTS: The mean follow-up time after silicone oil barrier suture operations was 12.0 ± 6.8 months. Silicone oil was present in the anterior chamber in five eyes (31%) at the last visit. These eyes also had hypotony, band keratopathy, and anterior proliferative vitreoretinopathy. CONCLUSION: In this study, silicone oil barrier sutures were proven to be safe and effective in preventing silicone oil-corneal endothelium touch in aphakic eyes with iris defects, unless hypotony was present because of anterior proliferative vitreoretinopathy

Delirium due to the use of topical cyclopentolate hydrochloride

PMID = 3205720

Choroidal Thickness, Photoreceptor Thickness, and Retinal Vascular Caliber Alterations in Dark Adaptation.

PURPOSE: Our aim was to evaluate the alterations of subfoveal choroidal thickness (SFCT), photoreceptor layer thickness (PRT), and retinal vessel diameter in the dark and light adaptation. METHODS: Twenty-four eyes of 24 healthy volunteers (12 males, 12 females) were included in this cross-sectional and observational study. The SFCT, PRT, retinal arteriole, and venule caliber measurements were performed with spectral domain optical coherence tomography in the dark (0.0 cd/m(2)) and under light (80 cd/m(2)) adapted conditions. RESULTS: The mean age of the participants was 30.4 ± 4.4 years (range: 22-42). The SFCT increased statistically significantly in dark adaptation (p 0.05). CONCLUSIONS: While SFCT increased, PRT, and retinal vessel diameter did not change following transition from light to dark

Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Patients with RetinalArtery Occlusion

Purpose: This study aimed to compare the neutrophil-to-lymphocyte (NLR) and plateletto- lymphocyte (PLR) ratios in patients with retinal artery occlusion (RAO) with those from a healthy control population and to identify the relationship between them. Methods: Forty-six patients with RAO and fifty-one healthy control subjects were included in this retrospective case-control study. RAO was diagnosed following an ophthalmic examination and fluorescein angiography (FA). Blood neutrophil, lymphocyte, and platelet counts were recorded for each of the 97 subjects, from which NLR and PLR values were calculated. Results: There were 46 patients (28 male [M], 18 female [F]) in the RAO group and 51 patients (27 M, 24 F) in the control group. No significant differences were found between patients with RAO and the control subjects in terms of gender and age (P > 0.05). Patients with RAO had significantly increased NLR values (2.85 ± 1.70) than the control subjects (1.63 ± 0.59, P < 0.001). The mean PLR in patients with RAO was 123.69 ± 64.98, while that in control subjects was 103.08 ± 36.95; there was no significant difference between the two groups (P = 0.055). A logistic regression analysis revealed that NLRs were 3.8 times higher in patients with RAO than in control subjects (odds ratio = 3.880; 95% confidence interval = 1.94 to 7.74; P < 0.001). Conclusion: NLRs were significantly increased in patients with RAO compared to the control subjects

Evaluation of retinal ganglion cell-inner plexiform layer complex in healthy smokers

PMID = 2766561