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We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic components. Several recent genome-wide association (GWA) studies in Caucasian samples have reported a number of gene regions and loci correlated with the risk of ASD—albeit with very little consensus across studies. Methods: A two-stage GWA study was employed to identify common genetic variants for ASD in the Taiwanese Han population. The discovery stage included 315 patients with ASD and 1,115 healthy controls, using the Affymetrix SNP array 6.0 platform for genotyping. Several gene regions were then selected for fine-mapping and top markers were examined in extended samples. Single marker, haplotype, gene-based, and pathway analyses were conducted for associations. Results: Seven SNPs had p-values ranging from 3.4~9.9*10−6, but none reached the genome-wide significant level. Five of them were mapped to three known genes (OR2M4, STYK1, and MNT) with significant empirical gene-based p-values in OR2M4 (p = 3.4*10−5) and MNT (p = 0.0008). Results of the fine-mapping study showed single-marker associations in the GLIS1 (rs12082358 and rs12080993) and NAALADL2 (rs3914502 and rs2222447) genes, and gene-based associations for the OR2M3-OR2T5 (olfactory receptor genes, p = 0.02), and GLIPR1/KRR1 gene regions (p = 0.015). Pathway analyses revealed important pathways for ASD, such as olfactory and G protein–coupled receptors signaling pathways. Conclusions: We reported Taiwanese Han specific susceptibility genes and variants for ASD. However, further replication in other Asian populations is warranted to validate our findings. Investigation in the biological functions of our reported genetic variants might also allow for better understanding on the underlying pathogenesis of autism. [ABSTRACT FROM AUTHOR]

Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness. [ABSTRACT FROM AUTHOR]

Runs of homozygosity (ROH) may play a role in complex diseases. In the current study, we aimed to test if ROHs are linked to the risk of autism and related language impairment. We analyzed 546,080 SNPs in 315 Han Chinese affected with autism and 1,115 controls. ROH was defined as an extended homozygous haplotype spanning at least 500 kb. Relative extended haplotype homozygosity (REHH) for the trait-associated ROH region was calculated to search for the signature of selection sweeps. Totally, we identified 676 ROH regions. An ROH region on 11q22.3 was significantly associated with speech delay (corrected p = 1.73×10−8). This region contains the NPAT and ATM genes associated with ataxia telangiectasia characterized by language impairment; the CUL5 (culin 5) gene in the same region may modulate the neuronal migration process related to language functions. These three genes are highly expressed in the cerebellum. No evidence for recent positive selection was detected on the core haplotypes in this region. The same ROH region was also nominally significantly associated with speech delay in another independent sample (p = 0.037; combinatorial analysis Stouffer’s z trend = 0.0005). Taken together, our findings suggest that extended recessive loci on 11q22.3 may play a role in language impairment in autism. More research is warranted to investigate if these genes influence speech pathology by perturbing cerebellar functions. [ABSTRACT FROM AUTHOR]

Purpose: To identify genetic variants that predispose to type 2 diabetes (T2D) with cataract. Patients and methods: Genome-wide association study (GWAS) of T2D patients with cataract, as graded by Lens Opacities Classification System (LOCS). A total of 109 T2D patients with cataract score equal to or above 10 designated as the study group, 649 T2D patients with cataract score equal to or below 3 as the control group. Single nucleotide polymorphisms (SNPs) with p-values < 10-5 were considered to be putatively associated with the diabetic cataract. Results: Fifteen SNPs were found to be putatively associated with diabetic cataract. These variants were located near the following genes: PPARD, CCDC102A, GBA3, NEDD9, GABRR1/2, RPS6KA2, tcag7.1163, TAC1, GALNTL1 and KIAA1671. We defined haplotype 1 to haplotype 4 from the alternative alleles of related polymorphisms. Distribution of haplotype 2 on chromosome 4 and haplotype 4 on chromosome 7 revealed significant differences (OR = 1.86 and 1.69, respectively; 95% confidence interval were 1.26-2.76 and 1.23-2.31, respectively). Conclusions: The 15 loci coded on chromosomes 4, 6, 7, 14, 16 and 22 were associated with diabetic cataract. Gene functions are either with mechanisms of regulating blood sugar or formation of cataract. High linkage disequilibrium appeared on chromosome 4p15.31 and chromosome 7q21.3. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is pediatric systemic vasculitis with the classic complication of coronary artery aneurysm (CAA). It is the leading cause of acquired cardiovascular diseases in children. Some severe cases present with multi-organ involvement or neurological dysfunction. To identify the role of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A) in KD, we investigated genetic variations in GRIN3A in a Taiwanese cohort of 262 KD patients (76 with and 186 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between clinical characteristics and GRIN3A genetic variations in KD. According to univariate regression analysis, CAA formation in KD was significantly associated with fever duration (p < 0.0001), first Intravenous immunoglobulin (IVIG) used (days after day one of fever) (p < 0.0001), and the GRIN3A (rs7849782) genetic variant (p < 0.001). KD patients with GG+GC genotype showed a lower rate of developing CAA (GG+GC genotype: odds ratio = 0.26; 95% CI = 0.14–0.46). Significant associations were identified between KD with CAA complication and the GRIN3A (rs7849782) genetic variant by using multivariate regression analysis. Specifically, significant correlations were observed between KD with CAA complications and the presence of GG+GC genotypes for the GRIN3A rs7849782 single-nucleotide polymorphism (full model: odds ratio = 0.25; 95% CI = 0.14–0.46). Our results suggest that a polymorphism of the GRIN3A gene may play a role in KD pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background: 3-Hydroxy-3-methylglutaryl CoA lyase deficiency (HL deficiency) is a rare autosomal recessive mitochondrial disease characterized by a deficiency in the enzyme 3-Hydroxy-3-methylglutaryl CoA lyase (HMGCL). Here, we report on novel mutations identified in the HMGCL gene in 2 Taiwanese patients with HL deficiency. Methods: Analysis of organic acids in urine was performed using gas chromatography-mass spectrometry to confirm HL deficiency in the two subjects. The mutations in their HMGCL genes then were determined by direct sequencing. In addition, the effect of a splice site mutation was determined using reverse transcription-polymerase chain reactions (RT-PCR). Results: A total of 3 novel mutations in the HMGCL gene were revealed by molecular analysis: one missense mutation (c.494G>T, p.Arg165Gln) and 2 splice site mutations (IVS3+1G>A, IVS6-1G>A). The results of RT-PCR revealed that an IVS3+1G>A mutation leads to skipping of exon3. We also calculated that the incidence of HL deficiency in Taiwan is <1 per 1,000,000 live births. Conclusions: The results of this study suggest that unique HMGCL gene mutations exist in Taiwanese HL deficiency patients. Therefore, HMGCL gene profiling may be useful in genetic counseling for families affected by HL deficiency. [Copyright &y& Elsevier]