Frequency-Dependent Changes of Local Resting Oscillations in Sleep-Deprived Brain

Sleep deprivation (SD) adversely affects brain function and is accompanied by frequency dependent changes in EEG. Recent studies have suggested that BOLD fluctuations pertain to a spatiotemporal organization with different frequencies. The present study aimed to investigate the frequency-dependent SD-related brain oscillatory activity by using the amplitude of low-frequency fluctuation (ALFF) analysis. The ALFF changes were measured across different frequencies (Slow-4: 0.027–0.073 Hz; Slow-5: 0.01–0.027 Hz; and Typical band: 0.01–0.08 Hz) in 24 h SD as compared to rested wakeful during resting-state fMRI. Sixteen volunteers underwent two fMRI sessions, once during rested wakefulness and once after 24 h of SD. SD showed prominently decreased ALFF in the right inferior parietal lobule (IPL), bilateral orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC), while increased ALFF in the visual cortex, left sensorimotor cortex and fusiform gyrus. Across the Slow-4 and Slow-5, results differed significantly in the OFC, DLPFC, thalamus and caudate in comparison to typical frequency band; and Slow-4 showed greater differences. In addition, negative correlations of behavior performance and ALFF patterns were found mainly in the right IPL across the typical frequency band. These observations provided novel insights about the physiological responses of SD, identified how it disturbs the brain rhythms, and linked SD with frequency-dependent alterations in amplitude patterns.     

Imputation of Exome Sequence Variants into Population- Based Samples and Blood-Cell-Trait-Associated Loci in African Americans: NHLBI GO Exome Sequencing Project

Researchers have successfully applied exome sequencing to discover causal variants in selected individuals with familial, highly penetrant disorders. We demonstrate the utility of exome sequencing followed by imputation for discovering low-frequency variants associated with complex quantitative traits. We performed exome sequencing in a reference panel of 761 African Americans and then imputed newly discovered variants into a larger sample of more than 13,000 African Americans for association testing with the blood cell traits hemoglobin, hematocrit, white blood count, and platelet count. First, we illustrate the feasibility of our approach by demonstrating genome-wide-significant associations for variants that are not covered by conventional genotyping arrays; for example, one such association is that between higher platelet count and an MPL c.117G>T (p.Lys39Asn) variant encoding a p.Lys39Asn amino acid substitution of the thrombpoietin receptor gene (p = 1.5 × 10⁻¹¹). Second, we identified an association between missense variants of LCT and higher white blood count (p = 4 × 10⁻¹³). Third, we identified low-frequency coding variants that might account for allelic heterogeneity at several known blood cell-associated loci: MPL c.754T>C (p.Tyr252His) was associated with higher platelet count; CD36 c.975T>G (p.Tyr325^∗) was associated with lower platelet count; and several missense variants at the α-globin gene locus were associated with lower hemoglobin. By identifying low-frequency missense variants associated with blood cell traits not previously reported by genome-wide association studies, we establish that exome sequencing followed by imputation is a powerful approach to dissecting complex, genetically heterogeneous traits in large population-based studies.     

Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy

Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7^th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC₂₀) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10^-4, 1.9x10^-13 and 5.0x10^-5, respectively), and NOS1 in African Americans (p = 2.3x10^-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.     

Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5–5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.     

Low-Frequency Coding Variants at 6p21.33 and 20q11.21 Are Associated with Lung Cancer Risk in Chinese Populations

Genome-wide association studies have successfully identified a subset of common variants associated with lung cancer risk. However, these variants explain only a fraction of lung cancer heritability. It has been proposed that low-frequency or rare variants might have strong effects and contribute to the missing heritability. To assess the role of low-frequency or rare variants in lung cancer development, we analyzed exome chips representing 1,348 lung cancer subjects and 1,998 control subjects during the discovery stage and subsequently evaluated promising associations in an additional 4,699 affected subjects and 4,915 control subjects during the replication stages. Single-variant and gene-based analyses were carried out for coding variants with a minor allele frequency less than 0.05. We identified three low-frequency missense variants in BAT2 (rs9469031, c.1544C>T [p.Pro515Leu]; odds ratio [OR] = 0.55, p = 1.28 × 10⁻¹⁰), FKBPL (rs200847762, c.410C>T [p.Pro137Leu]; OR = 0.25, p = 9.79 × 10⁻¹²), and BPIFB1 (rs6141383, c.850G>A [p.Val284Met]; OR = 1.72, p = 1.79 × 10⁻⁷); these variants were associated with lung cancer risk. rs9469031 in BAT2 and rs6141383 in BPIFB1 were also associated with the age of onset of lung cancer (p = 0.001 and 0.006, respectively). BAT2 and FKBPL at 6p21.33 and BPIFB1 at 20q11.21 were differentially expressed in lung tumors and paired normal tissues. Gene-based analysis revealed that FKBPL, in which two independent variants were identified, might account for the association with lung cancer risk at 6p21.33. Our results highlight the important role low-frequency variants play in lung cancer susceptibility and indicate that candidate genes at 6p21.33 and 20q11.21 are potentially biologically relevant to lung carcinogenesis.     

Power spectra of extinction in the fossil record

Recent Fourier analyses of fossil extinction data have indicated that the power spectrum of extinction during the Phanerozoic may take the form of 1/f noise, a result which, it has been suggested, could be indicative of the presence of `critical dynamics'' in the processes giving rise to extinction. In this paper we examine extinction power spectra in some detail, using family-level data from two widely available compilations. We find that although the average form of the power spectrum roughly obeys the 1/f law, the spectrum can be represented more accurately by dividing it into two regimes: a low-frequency one which is well fit by an exponential, and a high-frequency one in which it follows a power law with a 1/f² form. We give explanations for the occurrence of each of these behaviours and for the position of the crossover between them.     

A Weighted False Discovery Rate Control Procedure Reveals Alleles at FOXA2 that Influence Fasting Glucose Levels

Association signals in GWAS are usually prioritized solely by p values. Here, we attempt to improve the power of GWAS by using a weighted false discovery rate control procedure to detect associations of low-frequency variants with effect sizes similar to or even larger than those of common variants. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to test for association with fasting glucose levels in the Atherosclerosis Risk in Communities Study (ARIC) population. In addition to finding several previously identified sequence variations, we identified a low-frequency variant (rs1209523; minor allele frequency = 0.043) near FOXA2 that was associated with fasting glucose levels in European Americans (EAs) (n = 7428, p value = 1.3 × 10⁻⁵). The association between rs1209523 and glucose levels was also significant in African Americans (AAs) (n = 2029, p value = 6.7 × 10⁻³) of the ARIC and was confirmed by replication in both EAs and AAs of the Dallas Heart Study (n = 963 and 1571, respectively; p values = 5.3 × 10⁻³ and 5.8 × 10⁻⁴, respectively) and in EAs of the Cooper Center Longitudinal Study (n = 2862; p value = 1.6 × 10⁻²). A meta-analysis of these five populations yielded an estimated effect size of −1.31 mg/dl per minor allele (p value = 2.2 × 10⁻¹¹). This study reveals that there is a cache of less-frequent variants in GWAS arrays that can be identified via analytical approaches accounting for allele frequencies.     

The Strong Selective Sweep Candidate Gene ADRA2C Does Not Explain Domestication Related Changes In The Stress Response Of Chickens

Analysis of selective sweeps to pinpoint causative genomic regions involved in chicken domestication has revealed a strong selective sweep on chromosome 4 in layer chickens. The autoregulatory α-adrenergic receptor 2C (ADRA2C) gene is the closest to the selective sweep and was proposed as an important gene in the domestication of layer chickens. The ADRA2C promoter region was also hypermethylated in comparison to the non-selected ancestor of all domesticated chicken breeds, the Red Junglefowl, further supporting its relevance. In mice the receptor is involved in the fight-or-flight response as it modulates epinephrine release from the adrenals. To investigate the involvement of ADRA2C in chicken domestication, we measured gene expression in the adrenals and radiolabeled receptor ligand in three brain regions comparing the domestic White Leghorn strain with the wild ancestor Red Junglefowl. In adrenals ADRA2C was twofold greater expressed than the related receptor gene ADRA2A, indicating that ADRA2C is the predominant modulator of epinephrine release but no strain differences were measured. In hypothalamus and amygdala, regions associated with the stress response, and in striatum, receptor binding pIC50 values ranged between 8.1–8.4, and the level was not influenced by the genotyped allele. Because chicken strains differ in morphology, physiology and behavior, differences attributed to a single gene may be lost in the noise caused by the heterogeneous genetic background. Therefore an F₁₀ advanced intercross strain between White Leghorn and Red Junglefowl was used to investigate effects of ADRA2C alleles on fear related behaviors and fecundity. We did not find compelling genotype effects in open field, tonic immobility, aerial predator, associative learning or fecundity. Therefore we conclude that ADRA2C is probably not involved in the domestication of the stress response in chicken, and the strong selective sweep is probably caused by selection of some unknown genetic element in the vicinity of the gene.     

Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region±10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10⁻³) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15×10⁻⁵), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5×10⁻⁵) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20×10⁻⁵). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10⁻³) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.     

Insertion and deletion polymorphism in the alpha-2B adrenoceptor gene in pregnant women ripens gestational diabetes mellitus

There are no earlier studies that reported the association of the 12Glu9 polymorphism in the alpha-2B adrenoceptor (ADRA2B) gene with gestational diabetes mellitus (GDM). We examined the potential association between the ADRA2B gene insertion/deletion (I/D) polymorphism in the Saudi population with GDM. Pregnant women with GDM have been reported to exhibit the same susceptibility as that observed in type 2 diabetes mellitus (T2DM). We have selected I/D polymorphism of the ADRA2B gene located in chromosome 2q11.1 that has been extensively related to T2DM and cardiovascular diseases. This case–control study was conducted with 200 GDM and 300 non-GDM pregnant women. Genotyping of I/D polymorphism was performed by conventional PCR method. Biochemical analyses were found to be significantly different between GDM and non-GDM subjects (p < 0.05). Genotype (ID + DD vs II, p = 0.0002) and allele (D vs I, p = 0.0002) frequencies of the 12Glu9 polymorphism were found to be statistically significant. However, a significant difference was found between allele and genotypes of I/D polymorphism of the ADRA2B gene or the clinical characteristics of the subjects. Our results obtained in this study indicate the ADRA2B gene in the Saudi women was associated with the development of GDM.     

Noise analysis and relaxation experiments of transport of hydrophobic anions across lipid membranes at equilibrium and nonequilibrium

Under equilibrium and nonequilibnum steady-stale conditions the spectral intensity of current noise S_J(f) generated by the transport of hydrophobic unions across lipid bilayer membranes was investigated. The experimental results were compared with different reaction models S_J(f) showed a characteristic increase proportional to f² between frequency-independent tails at low and high frequencies. This gradient was found to be independent of applied voltage which indicates the contribution of a single voltage-dependent reaction step of ion translocation across the membrane From the shape of S_J(f) at low frequencies the rate constant of ion desorption from the membrane into the aqueous phase could be estimated. Unambiguous evidence for the application of a general model, which includes the coupling of slow ion diffusion in the aqueous phase to ion adsorption/desorption at the membrane interface, could not be obtained from the low-frequency shape of S_J(f). The shot noise of this ion transport determines the amplitude of S_J(f) at high frequencies which decreases with increasing voltage applied. Analysis of voltage-jump current-relaxation experiments and of current noise carried cut on one membrane yielded significant differences of the derived ion partition coefficient. This deviation is qualitatively described on the basis of incomplete reaction steps.     

Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10⁻³³; LPA:p<10⁻¹⁹; 1p13.3:p<10⁻¹⁷) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10⁻⁷). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.     

APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10⁻⁴) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10⁻³). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10⁻³). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10⁻⁴) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10⁻⁴) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10⁻⁴) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10⁻⁴). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10⁻⁴) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.     

Variants in GLIS3 and CRY2 are associated with type 2 diabetes and impaired fasting glucose in Chinese Hans

Background

Recent genome-wide association studies have identified a number of common variants associated with fasting glucose homeostasis and type 2 diabetes in populations of European origin. This is a replication study to examine whether such associations are also observed in Chinese Hans.

Methods

We genotyped nine variants in or near MADD, ADRA2A, CRY2, GLIS3, PROX1, FADS1, C2CD4B, IGF1 and IRS1 in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai.

Results

We confirmed the associations of GLIS3-rs7034200 with fasting glucose (beta = 0.07 mmol/l, P = 0.03), beta cell function (HOMA-B) (beta = −3.03%, P = 0.009), and type 2 diabetes (OR [95%CI]  = 1.27 [1.09–1.49], P = 0.003) after adjustment for age, sex, region and BMI. The association for type 2 diabetes remained significant after adjusting for other diabetes related risk factors including family history of diabetes, lipid profile, medication information, hypertension and life style factors, while further adjustment for HOMA-B abolished the association. The A-allele of CRY2-rs11605924 was moderately associated with increased risk of combined IFG/type 2 diabetes (OR [95%CI]  = 1.15[1.01–1.30], P = 0.04). SNPs in or near MADD, ADRA2A, PROX1, FADS1, C2CD4B, IGF1, and IRS1 did not exhibit significant associations with type 2 diabetes or related glycemic traits (P≥0.10).

Conclusions

In conclusion, our results indicate the associations of GLIS3 locus with type 2 diabetes and impaired fasting glucose in Chinese Hans, partially mediated through impaired beta-cell function. In addition, we also found modest evidence for the association of CRY2-rs11605924 with combined IFG/type 2 diabetes.     

Risk Alleles in/near ADCY5, ADRA2A,CDKAL1, CDKN2A/B,GRB10, and TCF7L2 Elevate Plasma Glucose Levels at Birth and in Early Childhood: Results from the FAMILY Study

BackgroundMetabolic abnormalities that lead to type 2 diabetes mellitus begin in early childhood.ObjectivesWe investigate whether common genetic variants identified in adults have an effect on glucose in early life.Methods610 newborns, 463 mothers, and 366 fathers were included in the present study. Plasma glucose and anthropometric characteristics were collected at birth, 3, and 5 years. After quality assessment, 37 SNPs, which have demonstrated an association with fasting plasma glucose at the genome-wide threshold in adults, were studied. Quantitative trait disequilibrium tests and mixed-effects regressions were conducted to estimate an effect of the SNPs on glucose.ResultsRisk alleles for 6 loci increased glucose levels from birth to 5 years of age (ADCY5, ADRA2A, CDKAL1, CDKN2A/B, GRB10, and TCF7L2, 4.85x10^-3 ≤ P ≤ 4.60x10^-2). Together, these 6 SNPs increase glucose by 0.05 mmol/L for each risk allele in a genotype score (P = 6.33x10^-5). None of the associations described in the present study have been reported previously in early childhood.ConclusionOur data support the notion that a subset of loci contributing to plasma glucose variation in adults has an effect at birth and in early life.     

Pathway-Based Genome-Wide Association Studies for Plasma Triglycerides in Obese Females and Normal-Weight Controls

Pathway-based analysis as an alternative approach can provide complementary information to single-marker genome-wide association studies (GWASs), which always ignore the epistasis and does not have sufficient power to find rare variants. In this study, using genotypes from a genome-wide association study (GWAS), pathway-based association studies were carried out by a modified Gene Set Enrichment Algorithm (GSEA) method (GenGen) for triglyceride in 1028 unrelated European-American extremely obese females (BMI≥35kg/m²) and normal-weight controls (BMI<25kg/m²), and another pathway association analysis (ICSNPathway) was also used to verify the GenGen result in the same data. The GO0009110 pathway (vitamin anabolism) was among the strongest associations with triglyceride (empirical P<0.001); the result remained significant after FDR correction (P = 0.022). MMAB, an obesity-related locus, included in this pathway. The ABCG1 and BCL6 gene was found in several triglyceride-related pathways (empirical P<0.05), which were also replicated by ICSNPathway (empirical P<0.05, FDR<0.05). We also performed single-marked GWAS using PLINK for TG levels (log-transformed). Significant associations were found between ASTN2 gene SNPs and plasma triglyceride levels (rs7035794, P = 2.24×10⁻¹⁰). Our study suggested that vitamin anabolism pathway, BCL6 gene pathways and ASTN2 gene may contribute to the genetic variation of plasma triglyceride concentrations.     

Impact of Measurement Error on Testing Genetic Association with Quantitative Traits

Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p<10⁻⁵) for the two cataract grading scales while replication results in genetic variants of blood pressure displayed no significant differences between averaged blood pressure measurements and single blood pressure measurements. We have developed a framework for researchers to quantify power in the presence of measurement error, which will be applicable to studies of phenotypes in which the measurement is highly variable.     

Genetic associations of common deletion polymorphisms in families with Avellino corneal dystrophy

Although the locations of many common deletion variants in the human genome are unknown, such deletions may be causative in rare disorders. Deletions can be mapped through the identification of Mendelian inconsistencies in pedigrees. Data for a total of 341,577 SNPs from an ACD family cohort (n = 551) and 341,039 SNPs from a Korean-Vietnamese family cohort (n = 554) were collected for a genome-wide association study using Illumina 370K-Duo Beadchips^®. In the present study, a Mendelian inconsistency analysis of genotype data identified 1029 deletion variants in Korean and Korean-Vietnam family cohorts of 404 trios comprising 1105 individuals. Small-deletion copy number variations adjacent to 10 deletion variants were then validated by the real-time quantitative polymerase chain reaction. The expected copy numbers of each deletion variant were directly matched to its genotype cluster image. Deletion variants were also in strong linkage disequilibrium with nearby SNPs. To determine the overall contribution of the 1029 deletion variants, we analyzed case-control trio associations with the risk for Avellino corneal dystrophy. One SNP marker (rs885945) neighboring the gene encoding major histocompatibility complex class I F (HLA-F) was significantly associated with the risk of Avellino corneal dystrophy (P = 0.0003). rs885945 showed high LD with SNPs within the HLA-F gene. Therefore, HLA-F may be a potential candidate gene for Avellino corneal dystrophy.