Testing the Reliability and Validity of the Korean Version of the Pittsburgh Sleep Quality Index Using Fitbit Devices: A Cross-Sectional Analysis.

Background: Sleep disorders and insomnia are prevalent worldwide, with negative health outcomes. The Pittsburgh Sleep Quality Index (PSQI) is a widely used self-report assessment tool for evaluating sleep quality, comprising seven subdomains. The Korean version of the PSQI (PSQI-K) has been tested for reliability and validity in small sample sizes but lacks large-scale validation using objective measures. Methods: This study was conducted with 268 Korean adults attending health check programs. Participants completed the PSQI-K questionnaire and wore Fitbit devices (Fitbit Inc., USA) to ascertain sleep parameters. Reliability was analyzed using the Cronbach's α coefficient, and construct validity was determined through factor analysis. Criteria validity was assessed by correlating their index scores with Fitbit sleep parameters. We identified the optimal cutoff for detecting sleep disorders. Results: The Cronbach's α coefficient was 0.61, indicating adequate internal consistency. Factor analysis revealed three factors, explaining 48.2% of sleep quality variance. The index scores were negatively correlated with Fitbit sleep efficiency, total sleep time, and number of awakenings (P<0.05). The optimal cutoff point for identifying sleep disorder groups was ≥6. Conclusion: The PSQI-K demonstrated good reliability and validity when correlated with Fitbit sleep parameters, offering a practical screening tool for identifying sleep disorders among Korean adults. Cutoff scores can help identify patients for sleep interventions. However, further large-scale studies are required to validate these findings.

Genetic Variants Linked to Myocardial Infarction in Individuals with Non-Alcoholic Fatty Liver Disease and Their Potential Interaction with Dietary Patterns.

In recent studies, non-alcoholic fatty liver disease (NAFLD) has been associated with a high risk of ischemic heart disease. This study aimed to investigate a genetic variant within a specific gene associated with myocardial infarction (MI) among patients with NAFLD. We included 57,205 participants from a Korean genome and epidemiology study. The baseline population consisted of 45,400 individuals, with 11,805 identified as patients with NAFLD. Genome-wide association studies were conducted for three groups: the entire sample, the healthy population, and patients with NAFLD. We defined the p-value < 1 × 10-5 as the nominal significance and the p-value < 5 × 10-2 as statistically significant for the gene-by-nutrient interaction. Among the significant single-nucleotide polymorphisms (SNPs), the lead SNP of each locus was further analyzed. In this cross-sectional study, a total of 1529 participants (2.8%) had experienced MI. Multivariable logistic regression was performed to evaluate the association of 102 SNPs across nine loci. Nine SNPs (rs11891202, rs2278549, rs13146480, rs17293047, rs184257317, rs183081683, rs1887427, rs146939423, and rs76662689) demonstrated an association with MI in the group with NAFLD Notably, the MI-associated SNP, rs134146480, located within the SORCS2 gene, known for its role in secreting insulin in islet cells, showed the most significant association with MI (p-value = 2.55 × 10-7). Our study identifies candidate genetic polymorphisms associated with NAFLD-related MI. These findings may serve as valuable indicators for estimating MI risk and for conducting future investigations into the underlying mechanisms of NAFLD-related MI.

Activated somatostatin interneurons orchestrate memory microcircuits.

Despite recent advancements in identifying engram cells, our understanding of their regulatory and functional mechanisms remains in its infancy. To provide mechanistic insight into engram cell functioning, we introduced a novel local microcircuit labeling technique that enables the labeling of intraregional synaptic connections. Utilizing this approach, we discovered a unique population of somatostatin (SOM) interneurons in the mouse basolateral amygdala (BLA). These neurons are activated during fear memory formation and exhibit a preference for forming synapses with excitatory engram neurons. Post-activation, these SOM neurons displayed varying excitability based on fear memory retrieval. Furthermore, when we modulated these SOM neurons chemogenetically, we observed changes in the expression of fear-related behaviors, both in a fear-associated context and in a novel setting. Our findings suggest that these activated SOM interneurons play a pivotal role in modulating engram cell activity. They influence the expression of fear-related behaviors through a mechanism that is dependent on memory cues.

Plasticity of Dendritic Spines Underlies Fear Memory.

The brain has the powerful ability to transform experiences into anatomic maps and continuously integrate massive amounts of information to form new memories. The manner in which the brain performs these processes has been investigated extensively for decades. Emerging reports suggest that dendritic spines are the structural basis of information storage. The complex orchestration of functional and structural dynamics of dendritic spines is associated with learning and memory. Owing to advancements in techniques, more precise observations and manipulation enable the investigation of dendritic spines and provide clues to the challenging question of how memories reside in dendritic spines. In this review, we summarize the remarkable progress made in revealing the role of dendritic spines in fear memory and the techniques used in this field.

Genome-wide association and replication studies for handedness in a Korean community-based cohort.

INTRODUCTION: Handedness is a conspicuous characteristic in human behavior, with a worldwide proportion of approximately 90% of people preferring to use the right hand for many tasks. In the Korean population, the proportion of left-handedness is relatively low at approximately 7%-10%, similar to that in other East-Asian cultures in which the use of the left hand for writing and other public activities has historically been oppressed. METHODS: In this study, we conducted two genome-wide association studies (GWASs) between right-handedness and left-handedness, and between right-handedness and ambidexterity using logistic regression analyses using a Korean community-based cohort. We also performed association analyses with previously reported variants and our findings. RESULTS: A total of 8806 participants were included for analysis, and the results identified 28 left-handedness-associated and 15 ambidexterity-associated loci; of these, two left-handedness loci (NEIL3 [rs11726465] and SVOPL [rs117495448]) and one ambidexterity locus (PDE8B/WDR41 [rs118077080]) showed near genome-wide significance. Association analyses with previously reported variants replicated ANKS1B (rs7132513) in left-handedness and ANKIB1 (rs2040498) in ambidexterity. CONCLUSION: The variants and positional candidate genes identified and replicated in this study were largely associated with brain development, cerebral asymmetry, neurological processes, and neuropsychiatric diseases in line with previous findings. As the first East-Asian GWAS related to handedness, these results may provide an intriguing reference for further human neurologic research in the future.

Increased social interaction in Shank2-deficient mice following acute social isolation.

Autism spectrum disorder (ASD) is neuropsychiatric disorder with a gender specific risk. Although social impairment in ASD is one of the well characterized phenotypes, loneliness issue resides in patients with ASD and emerging reports show gender distribution in symptoms. Acute social isolation increases the motivation to socially interact in a gender-dependent manner, as only the male mice show increase in sociability following isolation. However, it remains to be explored whether the effects of loneliness in ASD differ between genders. Here, we used Shank2-deficient (Shank2-/-) mice, one of the animal models of ASD, to examine the sociability changes after acute social isolation. While only the male wild-type (WT) mice display increased sociability following 24-h isolation, both sexes of Shank2-/- mice show an increase in social interaction following isolation. These observations provide evidence that animal models of ASD have the sensitivity to acute social isolation and further show the motivation to socially interact.

Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.

Although many genome-wide association studies (GWASs) have evaluated the association with metabolic disorders, the current study is the first attempt to analyze the genetic risk factors for various metabolic disorders according to sex and age groups of the life course in Korean adults. A total population of 50,808 people were included in this GWAS. The genetic traits for eight metabolic phenotypes were investigated in peri-, and postmenopausal women compared to a younger group or men of corresponding age groups. The metabolic phenotypes include general obesity, abdominal obesity, hypertension, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, hypo-high-density lipoprotein cholesterolemia, and metabolic syndrome. In the total participants, GWAS results for eight metabolic phenotypes found 101 significant loci. Of these, 15 loci were the first reported to be associated with the risk of metabolic disorder. Interestingly, some of the significant loci presented the association with the various phenotypes, which presented when there was a correlation between phenotypes. In addition, we analyzed divided by gender and age (young adult, peri-menopausal group, older adult), and specifically identified specific loci in peri-menopausal women. Meanwhile, several genetic factors associated with metabolic disorders were newly reported in our study. In particular, several genes were significantly associated with one of the metabolic phenotypes in only a single specific group. These findings suggest that menopausal transition rather than aging itself potentiates the influence of genetic risks on metabolic disorders. In addition, some genetic loci with low frequencies may play a role in the metabolic disturbances in a specific sex and age group. The genetic traits derived from our study may contribute to understanding the genetic risk factors for metabolic disorders in the Korean population.

Synaptic ensembles between raphe and D1R-containing accumbens shell neurons underlie postisolation sociability in males.

Social animals expend considerable energy to maintain social bonds throughout their life. Male and female mice show sexually dimorphic behaviors, yet the underlying neural mechanisms of sociability and their dysregulation during social disconnection remain unknown. Dopaminergic neurons in dorsal raphe nucleus (DRNTH) is known to contribute to a loneliness-like state and modulate sociability. We identified that activated subpopulations in DRNTH and nucleus accumbens shell (NAcsh) during 24 hours of social isolation underlie the increase in isolation-induced sociability in male but not in female mice. This effect was reversed by chemogenetically and optogenetically inhibiting the DRNTH-NAcsh circuit. Moreover, synaptic connectivity among the activated neuronal ensembles in this circuit was increased, primarily in D1 receptor-expressing neurons in NAcsh. The increase in synaptic density functionally correlated with elevated dopamine release into NAcsh. Overall, specific synaptic ensembles in DRNTH-NAcsh mediate sex differences in isolation-induced sociability, indicating that sex-dependent circuit dynamics underlie the expression of sexually dimorphic behaviors.

Classification of early age facial growth pattern and identification of the genetic basis in two Korean populations.

Childhood to adolescence is an accelerated growth period, and genetic features can influence differences of individual growth patterns. In this study, we examined the genetic basis of early age facial growth (EAFG) patterns. Facial shape phenotypes were defined using facial landmark distances, identifying five growth patterns: continued-decrease, decrease-to-increase, constant, increase-to-decrease, and continued-increase. We conducted genome-wide association studies (GWAS) for 10 horizontal and 11 vertical phenotypes. The most significant association for horizontal phenotypes was rs610831 (TRIM29; ß = 0.92, p-value = 1.9 × 10-9) and for vertical phenotypes was rs6898746 (ZSWIM6; ß = 0.1103, p-value = 2.5 × 10-8). It is highly correlated with genes already reported for facial growth. This study is the first to classify and characterize facial growth patterns and related genetic polymorphisms.

Dyslipidaemia-Genotype Interactions with Nutrient Intake and Cerebro-Cardiovascular Disease.

A comprehensive understanding of gene-diet interactions is necessary to establish proper dietary guidelines to prevent and manage cardio-cerebrovascular disease (CCD). We investigated the role of genetic variants associated with dyslipidaemia (DL) and their interactions with macro-nutrients for cardiovascular disease using a large-scale genome-wide association study of Korean adults. A total of 58,701 participants from a Korean genome and epidemiology study were included. Their dietary intake was assessed using a food frequency questionnaire. Dyslipidaemia was defined as total cholesterol (TCHL) ≥ 240 mg/dL, high-density lipoprotein (HDL) < 40 mg/dL, low-density lipoprotein (LDL) ≥ 160 mg/dL, triglycerides (TG) ≥ 200 mg/dL, or dyslipidaemia history. Their nutrient intake was classified as follows: protein intake: high ≥ 30%, 30% > moderate ≥ 20%, and 20% > low in daily total energy intake (TEI); carbohydrate intake: high ≥ 60%, 60% > moderate ≥ 50%, and 50% > low; fat intake: high ≥ 40%, 40% > moderate ≥ 30%, and 30% > low. Odds ratios and 95% confidence intervals were calculated after adjusting for age; sex; body mass index (BMI); exercise status; smoking status; alcohol intake; principal component 1 (PC1); principal component 2 (PC2); and intake of carbohydrates, fats, and proteins. This analysis included 20,596 patients with dyslipidaemia and 1027 CCD patients. We found that rs2070895 related to LIPC was associated with HDL-cholesterol. Patients with the minor allele (A) in rs2070895 had a lower risk of CCD than those carrying the reference allele (G) (odds ratio [OR] = 0.8956, p-value = 1.78 × 10−2). Furthermore, individuals consuming protein below 20% TEI with the LIPC reference allele had a higher risk of CCD than those with the minor allele (interaction p-value 6.12 × 10−3). Our findings suggest that the interactions of specific polymorphisms associated with dyslipidaemia and nutrients intake can influence CCD.

Effects of Single Nucleotide Polymorphisms and Mediterranean Diet in Overweight or Obese Postmenopausal Women With Breast Cancer Receiving Adjuvant Hormone Therapy: A Pilot Randomized Controlled Trial.

Background and Aims: Weight management is recommended in overweight or obese breast cancer patients, as they have an increased risk of cancer recurrence and poor prognosis. Furthermore, identifying the relationships between genetic factors and nutrition could help suggest possible individualized nutritional solutions in weight management. The objective of this pilot randomized controlled trial was to investigate the influence of two obesity-associated single nucleotide polymorphisms and the Mediterranean diet intervention on weight loss and modification of nutrient intake and metabolic parameters in overweight or obese, postmenopausal, breast cancer patients receiving adjuvant hormone therapy. Methods: Seventy-eight breast cancer patients were randomly assigned to the Mediterranean diet (MeDiet) group or control group, and seventy-one were finally analyzed. Body composition, nutrient intake, and metabolic parameters were assessed at baseline and after the 8-week intervention. Fat mass and obesity-associated (FTO) rs7185735 and melanocortin-4 receptor (MC4R) rs476828 variants were genotyped. Results: We found that both variants did not influence weight loss or improvement of metabolic parameters within the Mediterranean diet intervention. Intake of saturated fatty acid (SFA) and trans fat was significantly increased in C carriers compared with the TT genotype of MC4R rs476828 only in the control group (p = 0.002 for SFA; p = 0.016 for trans fat), whereas no significant difference was observed between genotypes in the MeDiet group. There were statistically significant interactions between MC4R rs476828 and dietary intervention for changes in SFA intake (p = 0.009) and trans fat intake (p = 0.049). Conclusion: Our data suggest that considering the effects of genotype may be more necessary when the Mediterranean diet is not followed and that this diet may have a protective role against the effects of certain genotypes. Further studies are required to determine the potential mechanism of the observed gene-diet interaction. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04045392].

The first broad replication study of SNPs and a pilot genome-wide association study for androgenetic alopecia in Asian populations.

BACKGROUND: Many candidate genes for androgenetic alopecia (AGA) have been identified in studies of the Caucasians and some Asian populations. AIMS: This study aimed to confirm the known susceptibility genes reported in previous studies and find additional candidate genes for high-risk individuals for AGA in Korean population. PATIENTS/METHODS: We recapitulated the previously reported SNPs and identified the novel Korean AGA risk genetic variants using a Korean hospital-based AGA case and control samples. The population was consisting of 494 individuals (275 AGA cases and 146 controls). Using the 800 K SNPs of precision medical research array (PMRA SNP microarray chip) and imputation-based SNPs, 12 previous GWAS reports for AGA and a total of 62 160 SNPs were examined in our study samples. Also, we conducted the genome-wide association study (GWAS) by the logistic regression analyses for AGA cases and controls with controlling the age as the covariates. RESULTS: Among the 62 160 SNPs, a total of 1143 SNPs in 76 gene regions showed weak replication tendency with the p-values <0.05 and same direction of effects. Additionally, the GWAS results showed 110 SNPs in 13 independent regions with the suggestive p-values <1.00 × 10-5 . The most significantly replicated SNP resided on chromosome 20, which were similar to other AGA replication studies including Chinese study. The GWAS identified two SNPs (rs11010734 and rs2420640) increasing the risk for AGA in our study population. CONCLUSIONS: Our study would be a reference of the non-European studies to better understand AGA in different populations and ancestral contexts.

Effect of Walking Steps Measured by a Wearable Activity Tracker on Improving Components of Metabolic Syndrome: A Prospective Study.

We compared the improvement in components of metabolic syndrome (MS) before and after lifestyle modification, as determined by daily step counts (on a wrist-worn Fitbit®) in participants with and without MS recruited from volunteers attending medical health checkup programs. A linear mixed model was used to analyze the change in MS components between participants with and without MS by group × time interaction. Multiple logistic regression analysis after adjustment for confounders was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) for improvements in MS components per 1000-steps/day increments. Waist circumference, triglycerides, fasting plasma glucose, and diastolic blood pressure were significantly different between participants with and without MS (group × time: p = 0.010, p < 0.001, p = 0.025, and p = 0.010, respectively). Multivariable-adjusted ORs (95% CI) of improvement in MS components per 1000-steps/day increments were 1.24 (1.01−1.53) in participants with and 1.14 (0.93−1.40) in participants without MS. Walking improved MS components more in individuals with than without MS. From a public health perspective, walking should be encouraged for high-risk MS individuals.

Identification of the interactions between specific genetic polymorphisms and nutrient intake associated with general and abdominal obesity in middle-aged adults.

BACKGROUND & AIMS: Comprehensive understanding of gene-diet interactions is necessary to establish proper dietary guidelines to prevent and manage general and abdominal obesity. We investigated the role of genetic variants and their interactions with general and abdominal obesity-associated nutrients using a largescale genome-wide association study of Korean adults. METHODS: A total of 50,808 participants from a Korean genome and epidemiology study were included. Dietary intake was assessed using a food frequency questionnaire. Obesity was defined as a body mass index ≥25 kg/m2. Abdominal obesity (AO) was defined as waist circumference ≥90 cm and 80 cm in males and females, respectively. Dietary nutrient intake was classified based on Korean Dietary Reference Intakes (DRIs). Odds ratios and 95% confidence intervals were calculated after adjusting for age, sex, exercise, smoking, alcohol drinking, total energy consumption, PC1, and PC2. RESULTS: Among the individuals consuming fat (%) above DRI, carriers of Ca binding protein 39 (CAB39)- rs6722579 minor allele (A) have a higher risk of AO than those not carrying the SNP (odds ration [OR] = 3.73, p-value = 2.05e-07; interaction p-value = 1.80e-07). Among the individuals consuming vitamin C above DRI, carriers of carboxypeptidase Q (CPQ)- rs59465035 minor allele (T) have a lower risk of AO than those without that SNP (OR = 0.89, p-value = 1.44e-08; interaction p-value = 9.50e-06). The genetic association with obesity was stronger among individuals with a genetic variant rs4130113 near GHR gene region in those consume folate above DRI and with a genetic variant rs5760920 near CRYBB2 gene region in those consume vitamin B2 above DRI. CONCLUSION: Our study results suggested that interactions of specific polymorphisms at loci and certain nutrients may influence obesity and abdominal obesity.

Genome-wide association of individual vulnerability with alcohol-associated liver disease: A Korean genome and epidemiology study.

BACKGROUND AND AIMS: The quantity of alcohol leading to alcohol-associated liver disease (ALD) varies individually. Genetic backgrounds contributing to the divergence in individual susceptibility to alcohol-induced liver damage have not been elucidated in detail. APPROACH AND RESULTS: Based on the Korean Genome and Epidemiology Study Health Examination (KoGES_HEXA) cohort data, 21,919 participants (40-79 years old) were included and divided into cases and controls based on the ALD diagnostic criteria proposed by the American College of Gastroenterology. Data generated by a genome wide-association study were analyzed using logistic regression to assess the risk of ALD development in nondrinkers, light drinkers, and heavy drinkers. We detected three loci, gamma-glutamyltransferase 1 (GGT1), zinc protein finger 827 (ZNF827) and HNF1 homeobox A (HNF1A), which were significantly associated with ALD risk. The GGT1 rs2006227 minor allele was strongly associated with all groups. Among the minor alleles of single nucleotide polymorphisms (SNPs) in HNF1A, rs1183910 had the strongest association with a protective effect from ALD in light drinkers. However, this association was not observed in heavy drinkers. Five SNPs on chromosome 11 showed suggestive significance in protective effects against ALD. CONCLUSIONS: SNPs, including HNF1A rs1183910 minor allele, are the most promising genetic candidates for protection against ALD. The expression of genes contributing to ALD development may be altered by the amount of alcohol consumed.

Interaction between the PNPLA3 Gene and Nutritional Factors on NAFLD Development: The Korean Genome and Epidemiology Study.

Genetic and nutritional factors contribute to the development of non-alcoholic fatty liver disease (NAFLD); however, gene-diet interactions in NAFLD development are poorly understood. In this case-control study, a large dataset from the Korean Genome and Epidemiology Study cohort (n = 72,299) comprising genomic data, medical records, social history, and dietary data was used. We investigated the interactions between the PNPLA3 rs738409 genotype and nutritional factors and their possible effect on the risk of NAFLD development in 2950 patients with NAFLD and 12,907 controls. In the PNPLA3 risk allele group, high protein, fat, sodium, phosphorus, niacin, and vitamin B6 intakes were associated with a decreased risk of NAFLD. In the non-risk allele group, only high fat intake was associated with a decreased risk of NAFLD. Among these nutrients, high sodium intake had a significant protective interaction with the PNPLA3 genotype against NAFLD (p = 0.002). Among salty foods, only kimchi had a significant protective effect against the PNPLA3 genotype (p = 0.012). Thus, the PNPLA3 genotype is differentially associated with nutritional factors. In particular, it interacts with kimchi, a fermented vegetable dish. Therefore, fermented vegetables may serve as a tailored therapeutic food for people with the PNPLA3 risk allele.

Abolished ketamine effects on the spontaneous excitatory postsynaptic current of medial prefrontal cortex neurons in GluN2D knockout mice.

Ketamine, a non-competitive antagonist of the N-methyl-D-aspartate receptor (NMDAR), generates a rapidly-acting antidepressant effect. It exerts psychomimetic effects, yet demands a further investigation of its mechanism. Previous research showed that ketamine did no longer promote hyperlocomotion in GluN2D knockout (KO) mice, which is a subunit of NMDAR. In the present study, we tested whether GluN2D-containing NMDARs participate in the physiological changes in the medial prefrontal cortex (mPFC) triggered by ketamine. Sub-anesthetic dose of ketamine (25 mg/kg) elevated the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in wild-type (WT) mice, but not in GluN2D KO mice, 1 h after the injection. The amplitude of sEPSC and paired-pulse ratio (PPR) were unaltered by ketamine in both WT and GluN2D KO mice. These findings suggest that GluN2D-containing NMDARs might play a role in the ketamine-mediated changes in glutamatergic neurons in mPFC and, presumably, in ketamine-induced hyperlocomotion.

Synaptic correlates of associative fear memory in the lateral amygdala.

Successful adaptation to the environment requires an accurate response to external threats by recalling specific memories. Memory formation and recall require engram cell activity and synaptic strengthening among activated neuronal ensembles. However, elucidation of the underlying neural substrates of associative fear memory has remained limited without a direct interrogation of extinction-induced changes of specific synapses that encode a specific auditory fear memory. Using dual-eGRASP (enhanced green fluorescent protein reconstitution across synaptic partners), we found that synapses among activated neuronal ensembles or activated synaptic ensembles showed a significantly larger spine morphology at auditory cortex (AC)-to-lateral amygdala (LA) projections after auditory fear conditioning in mice. Fear extinction reversed these enhanced synaptic ensemble spines, whereas re-conditioning with the same tone and shock restored the spine size of the synaptic ensemble. We suggest that synaptic ensembles encode and represent different fear memory states.

Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice.

Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia.

BACKGROUND: Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients. METHODS: We conducted a genome-wide association study (GWAS) of a multiple case-control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case-control group with 7,975,321 imputed single nucleotide polymorphisms using the Phase 3 Asian panel from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci. RESULTS: Totaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10-9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10-8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10-8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10-9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10-8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10-8]). CONCLUSIONS: This study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.