Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo.

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA-approved drug, effectively attenuated cyst formation in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

Case report: Expanding the phenotype of ARHGEF17 mutations from increased intracranial aneurysm risk to a neurodevelopmental disease.

RhoGTPase regulators play a key role in the development of the nervous system, and their dysfunction can result in brain malformation and associated disorders. Several guanine nucleotide exchange factors (GEF) have been linked to neurodevelopmental disorders. In line with this, ARHGEF17 has been recently linked as a risk gene to intracranial aneurysms. Here we report siblings of a consanguineous Pakistani family with biallelic variants in the ARHGEF17 gene associated with a neurodevelopmental disorder with intellectual disability, speech delay and motor dysfunction but not aneurysms. Cranial MRI performed in one patient revealed generalized brain atrophy with an enlarged ventricular system, thin corpus callosum and microcephaly. Whole exome sequencing followed by Sanger sequencing in two of the affected individuals revealed a homozygous missense variant (g.11:73021307, c.1624C>T (NM_014786.4), p.R542W) in the ARHGEF17 gene. This variant is in a highly conserved DCLK1 phosphorylation consensus site (I/L/V/F/M]RRXX[pS/pT][I/L/M/V/F) of the protein. Our report expands the phenotypic spectrum of ARHGEF17 variants from increased intracranial aneurysm risk to neurodevelopmental disease and thereby add ARHGEF17 to the list of GEF genes involved in neurodevelopmental disorders.

Gene-Environment Interactions in Face Categorization: Oxytocin Receptor Genotype x Childcare Experience Shortens Reaction Time.

Human faces capture attention, provide information about group belonging, and elicit automatic prepared responses. Early experiences with other-race faces play a critical role in acquiring face expertise, but the exact mechanism through which early experience exerts its influence is still to be elucidated. Genetic factors and a multi-ethnic context are likely involved, but their specific influences have not been explored. This study investigated how oxytocin receptor gene (OXTR) genotypes and childcare experience interacted to regulate face categorization in adults. Information about single nucleotide polymorphisms of OXTR (rs53576) and experiences with own- and other-race child caregivers was collected from 89 Singaporean adults, who completed a visual categorization task with own- versus other-race faces. Participants were grouped into A/A homozygotes and G carriers and assigned a score to account for their type of child caregiver experience. A multivariate linear regression model was used to estimate the effect of genetic group, child caregiver experience, and their interaction on categorization reaction time. A significant interaction of genetic group and child caregiver experience (t = 2.48, p = 0.015), as well as main effects of both genetic group (t = -2.17, p = 0.033) and child caregiver experience (t = -4.29, p < 0.001) emerged. Post-hoc analysis revealed that the correlation between categorization reaction time and child caregiver experience was significantly different between the two genetic groups. A significant gene x environment interaction on face categorization appears to represent an indirect pathway through which genes and experiences interact to shape mature social sensitivity to faces in human adults.

The Interaction between Serotonin Transporter Allelic Variation and Maternal Care Modulates Instagram Sociability in a Sample of Singaporean Users.

Human social interactions ensure recognition and approval from others, both in offline and online environments. This study applies a model from behavioral genetics on Instagram sociability to explore the impact of individual development on behavior on social networks. We hypothesize that sociable attitudes on Instagram resulted from an interaction between serotonin transporter gene alleles and the individual's social relationship with caregivers. We assess the environmental and genetic components of 57 Instagram users. The self-report questionnaire Parental Bonding Instrument is adopted to determine the quality of parental bonding. The number of posts, followed users ("followings"), and followers are collected from Instagram as measures of online social activity. Additionally, the ratio between the number of followers and followings ("Social Desirability Index") was calculated to estimate the asymmetry of each user's social network. Finally, buccal mucosa cell samples were acquired, and the polymorphism rs25531 (T/T homozygotes vs. C-carriers) within the serotonin transporter gene was examined. In the preliminary analysis, we identified a gender effect on the number of followings. In addition, we specifically found a gene-environment interaction on the standardized Instagram "Social Desirability Index" in line with our predictions. Users with the genotype more sensitive to environmental influences (T/T homozygotes) showed a higher Instagram "Social Desirability Index" than nonsensitive ones (C-carriers) when they experienced positive maternal care. This result may contribute to understanding online social behavior from a gene*environment perspective.

The relation between oxytocin receptor gene polymorphisms, adult attachment and Instagram sociability: An exploratory analysis.

Oxytocin is a primary neuropeptide which coordinates affiliative behavior. Previous researchers pointed to the association between genetic vulnerability on Oxytocin Receptor Gene (OXTR) and environmental factors (e.g., social relationships) to comprehend social behavior. Although an extensive knowledge of in-person social interactions has been obtained, little is known about online sociability. A gene-environment perspective is adopted to examine how OXTR and adult attachment moderate Instagram behavior. The genetic factors within the regions OXTR/rs53576 (A/A homozygotes vs G-carriers) and OXTR/rs2254298 (G/G homozygotes vs A-carriers) were assessed. The Experience in Close Relationships-Revised (ECR-R) questionnaire was used to collect participants' (N = 57, 16 males) attachment with a partner. The number of posts, followed people ("followings") and followers were obtained from Instagram, and the Social Desirability Index (SDI) was calculated as the ratio of followers to followings. Interaction effects between OXTR groups and ECR-R scores on the number of posts and SDI were hypothesized. Results showed an effect of rs53576 on the number of Instagram followings. Specifically, people with A/A OXTR/rs53576 genotype had more followings than G-carriers independent of the anxiety or avoidance felt towards their partner. These preliminary results offer insights into future investigations on social media behavior.

Modulation of Instagram Number of Followings by Avoidance in Close Relationships in Young Adults under a Gene x Environment Perspective.

Social networking sites have determined radical changes in human life, demanding investigations on online socialization mechanisms. The knowledge acquired on in-person sociability could guide researchers to consider both environmental and genetic features as candidates of online socialization. Here, we explored the impact of the quality of adult attachment and the genetic properties of the Serotonin Transporter Gene (5-HTTLPR) on Instagram social behavior. Experiences in Close Relationships-Revised questionnaire was adopted to assess 57 Instagram users' attachment pattern in close relationships with partners. Genotypes from the 5-HTTLPR/rs25531 region were extracted from the users' buccal mucosa and analyzed. Users' Instagram social behavior was examined from four indexes: number of posts, number of followed users ("followings") and number of followers, and the Social Desirability Index calculated from the followers to followings ratio. Although no interaction between rs25531 and ECR-R dimensions was found, an association between avoidance in close relationships and Instagram number of followings emerged. Post hoc analyses revealed adult avoidance from the partner predicts the Instagram number of followings with good evidence. Moreover, users reporting high avoidance levels displayed fewer followings than users who reported low levels of avoidance. This research provides a window into the psychobiological understanding of online socialization on Instagram.

High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy.

Leukodystrophies are a diverse group of genetic disorders that selectively involve the white matter of the brain and are a frequent cause of young-onset cognitive impairment. Genetic diagnosis is challenging. Data on the utility of incorporating brain magnetic resonance imaging (MRI) diagnostic algorithms with next-generation sequencing (NGS) for diagnosis in a real-life clinical setting is limited. We performed sequencing using a custom-designed panel of 200 neurodegeneration-associated genes on 45 patients with young-onset cognitive impairment with leukodystrophy, and classified them based on van der Knaap et al.'s MRI diagnostic algorithm. We found that 20/45 (44.4%) patients carried pathogenic variants or novel variants predicted to be pathogenic (one in CSF1R, two in HTRA1 and 17 in NOTCH3). All patients with an established genetic diagnosis had an MRI brain pattern consistent with a specific genetic condition/s. More than half (19/37, 51.4%) of patients with MRI changes consistent with vascular cognitive impairment secondary to small vessel disease (VCI-SVD) had pathogenic variants, including all patients with pathogenic NOTCH3 (17/19, 89.5%) and HTRA1 variants (2/19, 11.5%). Amongst patients harboring pathogenic NOTCH3 variants, 13/17 (76.5%) carried the p.R544C variant seen predominantly in East Asians. Anterior temporal white matter involvement was seen only in patients with pathogenic NOTCH3 variants (6/17, 35.3%). Overall, we demonstrated a high diagnostic utility incorporating a targeted neurodegeneration gene panel and MRI-based diagnostic algorithms in young-onset cognitive impairment patients with leukodystrophy.

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores. Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12). Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement.

To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10-29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.