Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

A robust and fast two-sample test of equal correlations with an application to differential co-expression.

A robust and fast two-sample test for equal Pearson correlation coefficients (PCCs) is important in solving many biological problems, including, for example, analysis of differential co-expression. However, few existing methods for this test can achieve robustness against deviation from normal distributions, accuracy under small sample sizes, and computational efficiency simultaneously. Here, we propose a new method for testing differential correlation using a saddlepoint approximation of the residual bootstrap (DICOSAR). To achieve robustness, accuracy, and efficiency, DICOSAR combines the ideas underlying the pooled residual bootstrap, the signed root of a likelihood ratio statistic, and a multivariate saddlepoint approximation. Through a comprehensive simulation study and a real data analysis of gene co-expression, we demonstrate that DICOSAR is accurate and robust in controlling the type I error rate for detecting differential correlation and provides a faster alternative to the bootstrap and permutation methods. We further show that DICOSAR can also be used for testing differential correlation matrices. These results suggest that DICOSAR provides an analytical approach to facilitate rapid testing for the equality of PCCs in large-scale analysis.

The heritability of BMI varies across the range of BMI-a heritability curve analysis in a twin cohort.

BACKGROUND: The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. METHOD/SUBJECTS: This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. RESULTS: The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. CONCLUSIONS: We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time.

Multivariate Generalized Linear Models for Twin and Family Data.

Multivariate twin and family studies are one of the most important tools to assess diseases inheritance as well as to study their genetic and environment interrelationship. The multivariate analysis of twin and family data is in general based on structural equation modelling or linear mixed models that essentially decomposes sources of covariation as originally suggested by  Fisher. In this paper, we propose a flexible and unified statistical modelling framework for analysing multivariate Gaussian and non-Gaussian twin and family data. The non-normality is taken into account by actually modelling the mean and variance relationship, while the covariance structure is modelled by means of a linear covariance model including the option to model the dispersion components as functions of known covariates in a regression model fashion. The marginal specification of our models allows us to extend classic models and biometric indices such as the bivariate heritability, genetic, environmental and phenotypic correlations to non-Gaussian data. We illustrate the proposed models through simulation studies and six data analyses and provide computational implementation in R through the package mglm4twin.

Familial risk and heritability of ischemic heart disease and stroke in Danish twins.

Aim: Our aim was to explore whether familial factors influence the risk of ischemic heart disease, stroke, and their co-occurrence. Methods: In total, 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry were followed from 1977 to 2011 in the Danish National Patient Registry for ischemic heart disease and stroke. Time-to-event analyses accounting for censoring and competing risk of death were used to estimate familial risk (casewise concordance relative to the cumulative incidence) and heritability of ischemic heart disease, stroke, and the co-occurrence by age. Results: During follow-up, we observed 5561 and 4186 twin individuals with ischemic heart disease and stroke respectively, with 936 twin pairs concordant for ischemic heart disease and stroke. Familial risks were significant for both, with higher cumulative risks in monozygotic than in dizygotic twins. Estimates for heritability were significant for ischemic heart disease as well as for stroke diagnosed after the age of 80. The casewise concordance of ischemic heart disease in twins whose co-twin was diagnosed with stroke did not differ for monozygotic and dizygotic twins; however, from age 55 it was 10% higher than the cumulative risk in the overall twin cohort and was 25% higher at age 90. A similar pattern was seen for stroke following the co-twin's ischemic heart disease. Conclusions: As in previous studies, we found a higher heritability of ischemic heart disease than of stroke. There was a significant familial risk but no heritability for the co-occurrence of ischemic heart disease and stroke. The co-occurrence is therefore likely due to other shared familial than genetic factors, highlighting that preventive initiatives should target families rather than individuals.

A Major Limitation of the Direction of Causation Model: Non-Shared Environmental Confounding.

Determining (1) the direction of causation and (2) the size of causal effects between two constructs is a central challenge of the scientific study of humans. In the early 1990s, researchers in behavioral genetics invented what was termed the direction of causation (DoC) model to address exactly these two concerns. The model claims that for any two traits whose mode of inheritance is sufficiently different, the direction of causation can be ascertained using a sufficiently large genetically informative sample. Using a series of simulation studies, we demonstrate a major challenge to the DoC model, namely that it is extremely sensitive to even tiny amounts of non-shared confounding. Even under ideal conditions for the DoC model (a large sample, N = 10,000), a large causal relationship (e.g., a causal correlation of .50) with very different modes of inheritance between the two traits (e.g., a pure AE model for one trait and a pure CE model for another trait) and a modest degree (correlation of .10) of non-shared confounding between the two traits results in the choice of the wrong causal models and estimating the wrong causal effects.

Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.

PURPOSE: Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). METHODS: Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. RESULTS: Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. CONCLUSION: Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017.

Mitral valve regurgitation in twins: Concordance and survival.

BACKGROUND: Smaller observational studies have suggested familial clustering of mitral regurgitation (MR). Using a large twin cohort, the aims were to assess MR concordance rates and assess mortality in MR twins and unaffected cotwins. METHODS: Through the Danish Twin Registry, twins with an International Classification of Diseases, Eighth Revision and Tenth Revision diagnosis code of MR born 1880-1989 were identified and proband-wise concordance rates were calculated. To assess whether having a cotwin with MR affected survival, 10 matched twins without MR (n = 5,575) were selected for each MR twin (n = 562), and all-cause mortality rates were assessed. RESULTS: Among the 87,432 twins alive January 1, 1977, or later, 494 (0.57%) MR individuals were identified. Six MR concordant pairs were found, of which 3 were monozygotic. Proband-wise concordance rate when accounting for right censoring and competing risk of death was 0.12 (95% CI 0.04-0.32) for monozygotic twins and 0.03 (95% CI 0.01-0.09) for dizygotic twins. Mortality was significantly higher among the affected twins with MR within discordant twin pairs where both were alive at the date of MR diagnosis (sex-adjusted hazard ratio [HR] 2.57, 95% CI 1.86-3.54). Overall there was no increased mortality risk for unaffected cotwins to MR cases compared with matched controls (HR 1.02, 95% CI 0.90-1.17) except for first year of life (HR 1.92, 95% CI 1.10-3.36) and for monozygotic twins older than 65 years (HR 1.49, 95% CI 1.07-2.08). CONCLUSION: Although there is a familial aggregation of MR, the absolute risk is low, even for monozygotic cotwins to affected twins. The study found increased mortality in MR twins compared with their unaffected cotwins. Overall no excess mortality was observed in the unaffected cotwins except for first year of life and for monozygotic cotwins older than 65 years.

Gene, environment and cognitive function: a Chinese twin ageing study.

BACKGROUND: the genetic and environmental contributions to cognitive function in the old people have been well addressed for the Western populations using twin modelling showing moderate to high heritability. No similar study has been conducted in the world largest and rapidly ageing Chinese population living under distinct environmental condition as the Western populations. OBJECTIVE: this study aims to explore the genetic and environmental impact on normal cognitive ageing in the Chinese twins. DESIGN/SETTING: cognitive function was measured on 384 complete twin pairs with median age of 50 years for seven cognitive measurements including visuospatial, linguistic skills, naming, memory, attention, abstraction and orientation abilities. Data were analysed by fitting univariate and bivariate twin models to estimate the genetic and environmental components in the variance and co-variance of the cognitive assessments. RESULTS: intra-pair correlation on cognitive measurements was low to moderate in monozygotic twins (0.23-0.41, overall 0.42) and low in dizygotic twins (0.05-0.30, overall 0.31) with the former higher than the latter for each item. Estimate for heritability was moderate for overall cognitive function (0.44, 95% CI: 0.34-0.53) and low to moderate for visuospatial, naming, attention and orientation abilities ranging from 0.28 to 0.38. No genetic contribution was estimated to linguistic skill, abstraction and memory which instead were under low to moderate control by shared environmental factors accounting for 23-33% of the total variances. In contrast, all cognitive performances showed moderate to high influences by the unique environmental factors. CONCLUSIONS: genetic factor and common family environment have a limited contribution to cognitive function in the Chinese adults. Individual unique environment is likely to play a major role in determining the levels of cognitive performance.

The genetic basis for cognitive ability, memory, and depression symptomatology in middle-aged and elderly chinese twins.

The genetic influences on aging-related phenotypes, including cognition and depression, have been well confirmed in the Western populations. We performed the first twin-based analysis on cognitive performance, memory and depression status in middle-aged and elderly Chinese twins, representing the world's largest and most rapidly aging population. The sample consisted of 384 twin pairs with a median age of 50 years. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) scale; memory was assessed using the revised Wechsler Adult Intelligence scale; depression symptomatology was evaluated by the self-reported 30-item Geriatric Depression (GDS-30)scale. Both univariate and multivariate twin models were fitted to the three phenotypes with full and nested models and compared to select the best fitting models. Univariate analysis showed moderate-to-high genetic influences with heritability 0.44 for cognition and 0.56 for memory. Multivariate analysis by the reduced Cholesky model estimated significant genetic (rG = 0.69) and unique environmental (rE = 0.25) correlation between cognitive ability and memory. The model also estimated weak but significant inverse genetic correlation for depression with cognition (-0.31) and memory (-0.28). No significant unique environmental correlation was found for depression with other two phenotypes. In conclusion, there can be a common genetic architecture for cognitive ability and memory that weakly correlates with depression symptomatology, but in the opposite direction.

The telomere lengthening conundrum--artifact or biology?

Recent longitudinal studies of age-dependent leukocyte telomere length (LTL) attrition have reported that variable proportions of individuals experience LTL lengthening. Often, LTL lengthening has been taken at face value, and authors have speculated about the biological causation of this finding. Based on empirical data and theoretical considerations, we show that regardless of the method used to measure telomere length (Southern blot or quantitative polymerase chain reaction-based methods), measurement error of telomere length and duration of follow-up explain almost entirely the absence of age-dependent LTL attrition in longitudinal studies. We find that LTL lengthening is far less frequent in studies with long follow-up periods and those that used a high-precision Southern blot method (as compared with quantitative polymerase chain reaction determination, which is associated with larger laboratory error). We conclude that the LTL lengthening observed in longitudinal studies is predominantly, if not entirely, an artifact of measurement error, which is exacerbated by short follow-up periods. We offer specific suggestions for design of longitudinal studies of LTL attrition to diminish this artifact.

Incidence and assessment of delirium following open cardiac surgery; A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis sought i) to provide an overview of the incidence of delirium following open cardiac surgery and ii) to investigate how incidences of delirium are associated with different assessment tools. METHODS AND RESULTS: A systematic search of studies investigating delirium following open cardiac surgery were conducted in Medline (Ovid), EMBASE, PsycINFO, CiNAHL and the Cochrane Database. Only studies with patients diagnosed or screened with a validated tool were included. Studies published from 2005 to 2021 were included in the meta-analysis.Of 7,126 individual studies retrieved, 106 met the inclusion criteria for the meta-analysis, hereof 31% of high quality. The weighted pooled incidence of delirium following open cardiac surgery across all studies was 23% (95% CI 20-26%), however we found a considerable heterogeneity (I2 = 99%), which could not be explained by subgroups or further sensitivity analyses. The most commonly applied screening tool for delirium is CAM/CAM-ICU. The lowest estimates of delirium were found by applying the Delirium Observation Scale (incidence 14%, 95% CI 8-20%), and the highest estimates in studies using "other" screening tools (Organic Brain Symptom Scale, Delirium Symptom Interview) pooled incidence of 43%, (95% CI 19 - 66%), however, only two studies applied these. CONCLUSION: Delirium following open cardiac surgery remains a complication with a high incidence of overall 23%, when applying a validated tool for screening or diagnosis. Nevertheless, this systematic review and meta-analyses highlight the significant inconsistency in current evidence regarding assessment tools and regimens. REGISTRATION: Prospero CRD42020215519.

Impact of a nationwide school policy on body mass index in Danish school children: An interrupted time series analysis.

Objectives: A new school policy mandating 45 min physical activity daily during school was introduced in Denmark in 2014. We aimed to evaluate the effect of this policy on BMI in school-aged children. It was hypothesized that the school policy would decrease BMI, especially in the obese fraction of the population (90th percentile BMI). Study design: This register-based study was conducted as a natural experiment. Methods: Analyses were based on data from The National Child Health Register that contains nationwide data on height and weight from mandatory preventive health examinations completed by school nurses or medical doctors during pre-preparatory classes (0th-3rd grade) and lower secondary education (7th-9th grade). A total of 401,517 children were included in the analyses with annual repeated cross-sectional data covering the period from 2012 to 2018. The effect of the school policy was evaluated using an interrupted time series approach comparing pre- and post-policy slopes in BMI, stratified by sex and age-group. Results: In boys, no significant differences were observed in mean BMI slopes from pre-to post-policy in either age-group. In girls, post-policy slopes were significantly higher compared to pre-policy in both age-groups (0th-3rd grade: ß:0·034 kg/m2, 95%-CI: (0·024; 0·043), p-value: <0·001; 7th-9th grade: ß:0·066 kg/m2, 95%-CI: (0·028; 0·103), p-value: 0·001). No significant differences in slopes were observed in BMI at the 90th percentile from pre-to post-policy for both sexes and across both age-groups. Adjustment for leisure-time physical activity as a potential time-varying confounder did not alter the findings. Conclusions: In conclusion, we did not detect a significant decrease in BMI levels among school-aged children following the introduction of a nationwide school policy specifying daily physical activity in school. If anything, a small positive change in BMI was observed in girls. More research is needed to understand whether structural changes similar to this requirement are able to prevent overweight and obesity in children and adolescents.

Leukocyte telomere dynamics in the elderly.

Limited data suggest that leukocytes of the elderly display ultra-short telomeres. It was reported that in some elderly persons leukocyte telomere length (LTL) shows age-dependent elongation. Using cross-sectional and longitudinal models, we characterized LTL dynamics in participants of the Longitudinal Study of Aging Danish Twins. We measured LTL by Southern blots of the terminal restriction fragment length (TRFL) in 476 individuals (73-94 years) in a cross-sectional evaluation and in a subset of this cohort comprising 80 individuals (73-81 years at baseline) who were followed-up for approximately 10 years. Based on the mean TRFL, we found that a) the average rate of LTL attrition was respectively, 27 bp/year (P < 0.001) and 31 bp/year (P < 0.001) for the cross-sectional and longitudinal evaluations, and b) mean TRFL was 180 bp (95 % CI 43, 320) longer in females than males (P < 0.010). For the TRFL distribution, which captures telomeres of all lengths in the DNA sample, we observed significant shifts with age toward shorter telomeres. Based on the measurement error of the TRFLs, we computed that in the longitudinal evaluation 10.6 % of individuals would manifest LTL elongation over 10 years, assuming a 340 bp attrition during this period. This was not significantly different from the empirical observation of 7.5 % of individuals showing LTL elongation. We conclude that accumulation of ultra-short telomeres in leukocytes of the elderly reflects a shift toward shorter telomeres in the entire telomere distribution. Measurement error is the probable explanation for LTL elongation in longitudinal studies.

Circulating microRNAs related to lipid metabolism and solid tissue maintenance and morphology associate with mortality in elderly twins.

The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy.

INTRODUCTION: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. METHOD: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. RESULTS: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. CONCLUSION: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

Familial Risk and Heritability of Hematologic Malignancies in the Nordic Twin Study of Cancer.

We aimed to explore the genetic and environmental contributions to variation in the risk of hematologic malignancies and characterize familial dependence within and across hematologic malignancies. The study base included 316,397 individual twins from the Nordic Twin Study of Cancer with a median of 41 years of follow-up: 88,618 (28%) of the twins were monozygotic, and 3459 hematologic malignancies were reported. We estimated the cumulative incidence by age, familial risk, and genetic and environmental variance components of hematologic malignancies accounting for competing risk of death. The lifetime risk of any hematologic malignancy was 2.5% (95% CI 2.4-2.6%), as in the background population. This risk was elevated to 4.5% (95% CI 3.1-6.5%) conditional on hematologic malignancy in a dizygotic co-twin and was even greater at 7.6% (95% CI 4.8-11.8%) if a monozygotic co-twin had a hematologic malignancy. Heritability of the liability to develop any hematologic malignancy was 24% (95% CI 14-33%). This estimate decreased across age, from approximately 55% at age 40 to about 20-25% after age 55, when it seems to stabilize. In this largest ever studied twin cohort with the longest follow-up, we found evidence for familial risk of hematologic malignancies. The discovery of decreasing familial predisposition with increasing age underscores the importance of cancer surveillance in families with hematological malignancies.

Novel DNA methylation marker discovery by assumption-free genome-wide association analysis of cognitive function in twins.

Privileged by rapid increase in available epigenomic data, epigenome-wide association studies (EWAS) are to make a profound contribution to understand the molecular mechanism of DNA methylation in cognitive aging. Current statistical methods used in EWAS are dominated by models based on multiple assumptions, for example, linear relationship between molecular profiles and phenotype, normal distribution for the methylation data and phenotype. In this study, we applied an assumption-free method, the generalized correlation coefficient (GCC), and compare it to linear models, namely the linear mixed model and kinship model. We use DNA methylation associated with a cognitive score in 400 and 206 twins as discovery and replication samples respectively. DNA methylation associated with cognitive function using GCC, linear mixed model, and kinship model, identified 65 CpGs (p < 1e-04) from discovery sample displaying both nonlinear and linear correlations. Replication analysis successfully replicated 9 of these top CpGs. When combining results of GCC and linear models to cover diverse patterns of relationships, we identified genes like KLHDC4, PAPSS2, and MRPS18B as well as pathways including focal adhesion, axon guidance, and some neurological signaling. Genomic region-based analysis found 15 methylated regions harboring 11 genes, with three verified in gene expression analysis, also the 11 genes were related to top functional clusters including neurohypophyseal hormone and maternal aggressive behaviors. The GCC approach detects valuable methylation sites missed by traditional linear models. A combination of methylation markers from GCC and linear models enriched biological pathways sensible in neurological function that could implicate cognitive performance and cognitive aging.

Generalized correlation coefficient for genome-wide association analysis of cognitive ability in twins.

Despite a strong genetic background in cognitive function only a limited number of single nucleotide polymorphisms (SNPs) have been found in genome-wide association studies (GWASs). We hypothesize that this is partially due to mis-specified modeling concerning phenotype distribution as well as the relationship between SNP dosage and the level of the phenotype. To overcome these issues, we introduced an assumption-free method based on generalized correlation coefficient (GCC) in a GWAS of cognitive function in Danish and Chinese twins to compare its performance with traditional linear models. The GCC-based GWAS identified two significant SNPs in Danish samples (rs71419535, p = 1.47e-08; rs905838, p = 1.69e-08) and two significant SNPs in Chinese samples (rs2292999, p = 9.27e-10; rs17019635, p = 2.50e-09). In contrast, linear models failed to detect any genome-wide significant SNPs. The number of top significant genes overlapping between the two samples in the GCC-based GWAS was higher than when applying linear models. The GCC model identified significant genetic variants missed by conventional linear models, with more replicated genes and biological pathways related to cognitive function. Moreover, the GCC-based GWAS was robust in handling correlated samples like twin pairs. GCC is a useful statistical method for GWAS that complements traditional linear models for capturing genetic effects beyond the additive assumption.