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The rapid development of sequencing technology and simultaneously the availability of large quantities of sequence data provide an unprecedented opportunity for researchers to conduct studies to detect rare variants associated with the disease. However, none of the current existing statistical methods has uniform power in all scenarios because they are more or less affected by nonfunctional variants and variants with opposite effects. Here, we present a robust approach to identify rare variants using weighted entropy theory. Here, this approach takes the proportion of the minor allele among all k variants as its probability distribution, which reduces the noise incurred by noncausal variants, and uses a weight to strike a balance between deleterious rare variants and protective rare variants, which makes our method impacted less by variants with opposite effect. Through simulation studies, we investigate the performance of our method for rare variant association analyses as well as for common variant association analyses and compared it with Burden test and the SKAT. Simulation studies show that the proposed method is valid and affected slightly by noncausal variants and opposite effect variants with high and stable power for various parameters set. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that circadian dysfunction is related to Parkinson's disease (PD). However, the role of circadian clock genes in PD is still poorly understood. This study aimed to illustrate the association between genetic variants of circadian clock genes and PD in a large Chinese population cohort. Ten circadian clock genes were included in this study. Whole-exome sequencing (WES) was conducted in 1997 early-onset or familial PD patients and 1652 controls (WES cohort), and whole-genome sequencing (WGS) was conducted in 1962 sporadic late-onset PD patients and 1279 controls (WGS cohort). Analyses were completed using the optimized sequence kernel association test and regression analyses. In the burden analysis of the circadian clock gene set, we found suggestive significant associations between the circadian clock genes and PD in the WES cohort when considering missense, damaging missense (Dmis), and deleterious variants. Moreover, the burden analysis of single genes revealed suggestive significant associations between PD and the loss-of-function variants of the CRY1 gene, missense, Dmis, and deleterious variants of the PER1 gene, and Dmis and deleterious variants of the PER2 gene in the WES cohort. Rare variants in the WGS cohort and all common variants in the WGS and WES cohorts were unrelated to PD. Phenotypic analysis indicated that deleterious variants of the PER1 gene were associated with dyskinesia in the WES cohort. Our study provides evidence of a potential link between circadian clock genes and PD from a genetic perspective. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that one variant can affect multiple traits, which is a widespread phenomenon in complex diseases. Joint analysis of multiple traits can increase statistical power of association analysis and uncover the underlying genetic mechanism. Although there are many statistical methods to analyse multiple traits, most of these methods are usually suitable for detecting common variants associated with multiple traits. However, because of low minor allele frequency of rare variant, these methods are not optimal for rare variant association analysis. In this paper, we extend an adaptive combination of P values method (termed ADA) for single trait to test association between multiple traits and rare variants in the given region. For a given region, we use reverse regression model to test each rare variant associated with multiple traits and obtain the P value of single-variant test. Further, we take the weighted combination of these P values as the test statistic. Extensive simulation studies show that our approach is more powerful than several other comparison methods in most cases and is robust to the inclusion of a high proportion of neutral variants and the different directions of effects of causal variants. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia. Numerous genome-wide association studies (GWASs) have found several AD susceptibility common loci but with limited effect size. Recent next-generation sequencing studies of large AD pedigrees had identified phospholipase D3 ( PLD3) p.V232M as the potentially functional rare variant with causal effect. However, four follow-up replication studies ( Brief Communications Arising on Nature) questioned that PLD3 V232M might not be so important in AD. In this study, we re-analyzed all public-available genetic (rare and common variants) and expression data of PLD3, and screened coding variants within PLD3 in probands of 18 Han Chinese families with AD, to clarify the exact involvement of PLD3 in AD. Two closest homologues of PLD3, PLD1 and PLD2, were also analyzed to comprehensively understand the role of phospholipase D members in AD. We found that PLD3 variant V232M was associated with AD risk in overall sample sets (∼40,000 subjects) with a modest to moderate effect size (odds ratio [OR] = 1.53). Our results also showed that common variants and mRNA expression alterations of PLD2 play a role in AD genetic risk and pathology. Although we provided a systematic view of the involvement of PLD3 in AD at the genetic, mRNA expression, and protein levels, we could not define the exact causal or essential role of PLD3 rare variants in AD based on currently available data. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD). With the sole exception of the APOE gene, these AD susceptibility genes have not been unequivocally validated in independent studies. No single novel functional risk genetic variant has been identified. In this review, we evaluate recent GWASs of AD, and discuss their significance, limitations, and challenges in the investigation of the genetic spectrum of AD. [ABSTRACT FROM AUTHOR]

Here, we investigate the association of common polymorphisms of the NOS1AP gene with sudden unexplained nocturnal death syndrome (SUNDS) in the southern Chinese Han population. We genetically screened five common NOS1AP polymorphisms (rs10918594, rs12143842, rs16847548, rs12567209, and rs10494366) previously reported to be associated with QT interval variation and sudden cardiac death (SCD) in 123 sporadic SUNDS cases and 166 healthy controls using polymerase chain reaction (PCR) and direct DNA sequencing. In the present study, the A allele of rs12567209 was more common in controls than in SUNDS cases, which was associated with 0.656-fold decreased risk of SUNDS (95 % confidence interval 0.431 to 0.998, P = 0.048) compared with G allele. Under the dominant genetic model, GA + AA genotype of rs12567209 was also more common in controls than in SUNDS cases, which was associated with 0.604-fold decreased risk of SUNDS (95 % confidence interval 0.368 to 0.991, P = 0.045) compared with GG genotype. No significant associations of rs10918594, rs12143842, rs16847548, and rs10494366 with SUNDS were observed ( P > 0.05). In haplotype analyses, the distribution of haplotype GCTA was significantly overrepresented in controls compared to SUNDS cases ( P = 0.040). This is the first report of the association of common NOS1AP polymorphisms with SUNDS in the southern Chinese Han population. These findings suggest that the A allele of rs12567209 and haplotype GCTA may serve as a protective modifier. [ABSTRACT FROM AUTHOR]

The genetic architecture of Autism Spectrum Disorders (ASD) is complex. Common genetic variation has especially been related to high-functioning ASD. In addition, some studies favoured analysis of strictly diagnosed autism individuals, which resulted in more robust findings than the combined analysis of all spectrum individuals. Functional variants modulating EIF4E expression have previously been indicated as risk factors for ASD. Pharmacological modulation of glutamate receptors which regulate EIF4E activity resulted in reduced repetitive behaviours in human and animal studies. Based on these findings, we tested common EIF4E variants for association with overall ASD, with strict autism and with the strict high-functioning autism (strict HFA) subgroup, and their effect on repetitive and/or stereotypic behaviour. We observed over-transmission of rs13109000G in the strict HFA and the strict autism cohort but not in the larger ASD cohort. We report protective effects for the minor allele of rs4699369T on stereotyped and ritualized behaviour in the overall ASD cohort, the strict autism but not in the strict HFA group. In addition, a protective role for rs4699369T and a risk effect of rs12498533G on hand and finger mannerisms was observed. These results need to be replicated in larger ASD and strict autism samples. The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD. [ABSTRACT FROM AUTHOR]

We investigated the predictive power of morphological features in 224 autistic patients and 224 matched-pairs controls. To assess the relationship between the morphological features and autism, we used the receiver operator curves (ROC). In addition, we used recursive partitioning (RP) to determine a specific pattern of abnormalities that is characteristic for the difference between autistic children and typically developing controls. The present findings showed that morphological features are significantly increased in patients with autism. Using ROC and RP, some of the morphological measures also led to strong predictive accuracy. Facial asymmetry, multiple hair whorls and prominent forehead significantly differentiated patients with autism from controls. Future research on multivariable risk prediction models may benefit from the use of morphological features. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus. We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort. We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs ( $$ p = 3.8 \times 10^{ - 7} $$ ; OR 1.43 [95% CI 1.24–1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance ( p = 0.053; OR 1.11 [95% CI 1.00–1.24]) in the present study. We also obtained several additional nominal association signals ( p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result ( p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04). Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility. [ABSTRACT FROM AUTHOR]