Statistical Genetics

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Sugarcane breeding all over the world aims at improving cane yield and sugar content to get new varieties that gets into the market. Kenya is not left out since the demand by the stakeholders in the Kenya sugar industry for new improved sugarcane varieties is high. The economic value of improving such sugarcane traits has not been incorporated in many of the sugarcane selection program including the one for Kenya Sugar Research Foundation (KESREF). This research was designed to construct an economic selection index that combines both cane and sugar yields according to their economic values. Breeding experimental trial was established and the convectional KESREF sugarcane breeding program followed from stage 1 to 5, though the selection index was used in stage 3 to 5.A randomized complete block (RCBD) was used in all the stages to randomize the treatments and agronomic and quality traits data were collected. An Analysis of Variance was performed to estimate the heritability, genotypi...

You yourself, or what is the same, your experience is such ``coin'' that, while you aren't questioned, it rotates all the time in ``free flight''. And only when you answer the question the ``coin'' falls on one of the sides: ``Yes'' or ``No'' with the believability that your experience tells you.

The paper addresses many important aspects of the issue of genetic psychopathy and the importance of more studies in the area of psychopathy itself. And, the impact of clinical psychopaths upon society as a clear and present danger are also noted within this paper. This is an important work.

In order to get to the point where one would understand just what his statement actually meant and referred to, one would have to know much about the true nature of royalty. And, that, is a very complex subject. As I have been explaining in other papers, just as we have a 1% today, this same “condition” existed for a very long time – a very long time. And the reason that it had remained so, is because those ancient royal individuals saw to it that it would; by creating many methods and means in which to secure that position for their own kind or 'race' (the condition, is now called 'Royal Supremacy'). [II]

What I have been educating people to is the existence of a ancient (unified) royal oligarchy. [III] They saw themselves as a separate race. That's right. A separate 'race'; the royal race. [IV] And, as I had said, this has been so for a very long time. The creation of an 'empire' where even 'officially' and publicly, the leaders of the religious faction helped to secure that position for the elite within that system, was created when the Holy Roman Empire was created (and actually, even before that time). [V]

Modelling growth of an animal is a complex process, because it requires describing longitudinal measurements with few
parameters with biological interpretation. With longitudinal data, the variance of observations may increase with time (age), and
repeated measurements of an individual over time are correlated. The non-independence of data violates a key assumption underlying
many statistical procedures and has been ignored in most traditional non-linear fixed effect models. A solution to this problem is the
use of non-linear mixed effect models (NLMM). A NLMM makes it possible to account for random covariates before testing for
fixed effects and control autocorrelation in repeated measures. In this study, growth data of Goat has been used. Attempt has been
made to develop the Von-bertalanffy mixed model. Logistic, Gompertz and Von-bertalanffy fixed and mixed models have also been
explored for these data. Comparison of the models i.e. between fixed and mixed type of the same model and among different fixed
and mixed models has been attempted. The goodness of fit statistics like i.e. Mean Square Error (MSE) and Root Mean Square Error
(RMSE) of the fitted models has been computed. The parameters of the best fitted models along with their corresponding standard
error are estimated. The performance of mixed effect models was found to be better than the fixed effect model. Specifically, under
the category of mixed effect model, the Logistic model out performed over the other types that were considered in the study.

Esta investigación presenta la propuesta filosófica de Xavier Zubiri como nuevo paradigma desde el que definir el desarrollo orgánico y comprender el dinamismo del embrión preimplantatorio. Además, pone de manifiesto las ambigüedades terminológicas que acompañan a las explicaciones sobre el hecho biológico en las descripciones científicas y en las reflexiones de carácter interdisciplinar. En la investigación se expone la teoría de la sustantividad y de la esencia de Xavier Zubiri, y se describe minuciosamente el desarrollo del embrión preimplantatorio a la luz de los datos científicos actuales, prestando especial atención a la epigénesis. La investigación muestra que desde el planteamiento zubiriano se puede, por un lado, describir con precisión la imbricación entre lo genético y lo epigenético y, por otro lado, definir, sin perder la unidad del organismo, la noción de desarrollo. Además, se realiza un análisis crítico de las principales posturas sobre el estatus ontológico del embrión humano y se muestra las ventajas de su abordaje desde el prisma zubiriano.

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved ...

The logic of uncertainty is not the logic of experience and as well as it is not the logic of chance. It is the logic of experience and chance. Experience and chance are two inseparable poles. These are two dual reflections of one essence, which is called co∼event. The theory of experience and chance is the theory of co∼events. To study the co∼events, it is not enough to study the experience and to study the chance. For this, it is necessary to study the experience and chance as a single entire, a co∼event. In other words, it is necessary to study their interaction within a co∼event. The new co∼event axiomatics and the theory of co∼events following from it were created precisely for these purposes. In this work, I am going to demonstrate the effectiveness of the new theory of co∼events in a studying the logic of uncertainty. I will do this by the example of a co∼event splitting of the logic of the Bayesian scheme, which has a long history of fierce debates between Bayesionists and frequentists. I hope the logic of the theory of experience and chance will make its modest contribution to the application of these old dual debaters.

Keywords: Eventology, event, probability, probability theory, Kolmogorov’s axiomatics, experience, chance, cause, consequence, co∼event, set of co∼events, bra-event, set of bra-events, ket-event, set of ket-events, believability, certainty, believability theory, certainty theory, theory of co∼events, theory of experience and chance, co∼event dualism, co∼event axiomatics, logic of uncertainty, logic of experience and chance, logic of cause and consequence, logic of the past and the future, Bayesian scheme.

Eventology of multivariate statistics
Eventology and mathematical eventology
Philosophical eventology and philosophy of probability
Practical eventology
Eventology of safety
Eventological economics and psychology
Mathematics in the humanities, socio-economic and natural sciences
Financial and actuarial mathematics
Multivariate statistical analysis
Multivariate complex analysis
Decision-making under risk and uncertainty
Risk measurement and risk models
Theory of fuzzy events and generalized theory of uncertainty
System analysis and events management

EEC'2016 ~ workshop on axiomatizing experience and chance, and Hilbert's sixth problem

With topics from quantum physics, probability and believability to economics, sociology and psychology, the workshop will be intended for an interdisciplinary discussion on mathematical theories of experience and chance. Topics of discussion include the results, thoughts and ideas on axiomatization of the eventological theory of experience and chance in the framework of the decision of Hilbert sixth problem.
Eventology of experience and chance
Beleivability theory and statistics of experience
Probability theory and statistics of chance
Axiomatizing experience and chance

Sharp upper and lower bounds are established for the modes of the Poisson distribution of order k. The lower bound established in this paper is better than the previously established lower bound. In addition, for k = 2, 3, 4, 5, a recent conjecture is presently proved solving partially an open problem since 1983.

Sugarcane breeding all over the world aims at improving cane yield and sugar content to get new varieties that gets into the
market. Kenya is not left out since the demand by the stakeholders in the Kenya sugar industry for new improved sugarcane varieties
is high. The economic value of improving such sugarcane traits has not been incorporated in many of the sugarcane selection program
including the one for Kenya Sugar Research Foundation (KESREF). This research was designed to construct an economic selection
index that combines both cane and sugar yields according to their economic values. Breeding experimental trial was established and the
convectional KESREF sugarcane breeding program followed from stage 1 to 5, though the selection index was used in stage 3 to 5.A
randomized complete block (RCBD) was used in all the stages to randomize the treatments and agronomic and quality traits data were
collected. An Analysis of Variance was performed to estimate the heritability, genotypic and phenotypic variance-covariances for the
measured trait. The economic values of the breeding traits were also established hence an economic selection index constructed.
Results showed that when the index is used in selection process, a decision of selecting superior clones based on both yield and sugar
content does no deviate much from the current selection criteria though it is robust to any future changes in the sugar industry.

"Nutritional genomics forms part of the genomic sciences and
addresses the interaction between genes and the human diet, its influence on metabolism and
subsequent susceptibility to develop common diseases. It encompasses both nutrigenomics,
which explores the effects of nutrients on the genome, proteome and metabolome; and
nutrigenetics, that explores the effects of genetic variations on the diet/disease interaction. A
number of mechanisms drive the gene/diet interaction: elements in the diet can act as links for
transcription factor receptors and alter intermediary concentrations, thereby modifying
chromatin and impacting genetic regulation; affect signal pathways, regulating
phosphorylation of tyrosine in receptors; decrease signaling through the inositol pathway; and
act through epigenetic mechanisms, silencing DNA fragments by methylation of cytosine. The
signals generated by polyunsaturated fatty acids are so powerful that they can even bypass
insulin mediated lipogenesis, stimulated by carbohydrates. Some fatty acids modify the
expression of genes that participate in fatty acid transport by lipoproteins. Nutritional genomics
has myriad possible therapeutic and preventive applications: in patients with enzymatic
deficiencies; in those with a genetic predisposition to complex diseases such as dyslipidemia,
diabetes and cancer; in those that already suffer these diseases; in those with altered mood or
memory; during the aging process; in pregnant women; and as a preventive measure in the
healthy population."

"Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.

Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.

Results: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10−6) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10−5). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.

Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.
"

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environment...

Please click here http://singledrug.com/media/Temporal_Analysis_of_Aging_description.pdf to see it.

I plan to add the following:

I found Osh6 at a very high rank of lifespan extending genes.  That is why I want to take all the genes that are part of the same molecular function as Osh6 and run an expression similarity analysis on SPELL (Serial Pattern of Expression Levels Locator) (see spell.yeastgenome.org/). 

I hope to find genes of unknown functions that could be involved in the same molecular function.  If I find this, I'll validate with my time series plots and TFBS similarity analysis.  That way I hope to predict the function of an unknown gene in lipid metabolism.  I will also try the opposite approach, i.e. I'll take genes of unknown function and look for a group of similarly expressed genes, which belong to the same GO term.

I added 19 pages to the second chapter.  I was able to further improve the accuracy of my yeast lifespan predicting machine learning algorithm by adding more features about lipids.  My last draft had an average prediction error of +/-5 replications.  Now it is less than +/-3 replication for the 50th percentile of the replicative lifespan.  To my knowledge nobody has published any research on about using machine learning and feature selection to predict the replicative age.

If you have any more ideas how I could make my dissertation look better, I'd be very thankful for any new feasible ideas and inspirations.  I have mainly been using Python and R for all my analysis.

I found that ribosomal RNA and proteins are most closely follow the cell cycle and that if knocked out the yeast's lifespan can be extended significantly.  I want to use the different cyclical periodically recurring and highly fluctuating gene expression oscillation pattern to discover the functions of genes we have not yet discovered.  I am interested in this because a friend of mine showed me a cancer dataset that looked very similar.  Since cancer is very similar to the yeast in that it keeps constantly dividing and hence its age can be expressed in replication we could use the same guilt-by-association approach to infer the functions or at least the way their expression is controlled by TFs from genes with similar temporal expression patterns of genes with already known functions.

When analyzing the time series plots of the 62 yeast chaperons I discovered that their expression plot trajectories can easily be clustered into 7 expression patterns, which are consisted with the 7 classes of yeast chaperons.  If I had only taken the average centroid of all 62 chaperons I would have been misled because using this approach could not be applied to potentially discover more new currently still unknown chaperons because no unknown chaperon would have time series trajectories, which would highly correlate with the average chaperon expression pattern of all 7 classes since their in-group expression pattern is very homogeneous but between the 7 different chaperon classes the expression pattern is very different.

I intended to elucidate the different ways by which we age by a very similar clustering algorithm, which I have developed based on time series curves over three subsequent yeast cell cycle consisting of 36 mRNA measures each about 25 minutes apart; thus, allowing to measure very steep mRNA expression fluctuation periods by manifold within the only 90 minutes of the cell cycle because even very brief but rapid expression changes that last not much longer than 1/12th of a cell cycle, of which I found surprisingly many.

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously.
Results: In this manuscript, we describe LD Hub-a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP herit-ability and the genetic correlation across the different phenotypes. We also present new results obtained by 2 uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. Availability and implementation: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/

A joint evaluation of all animals, uses all additive genetic relationships uses all data on all animal jointly It works as a linear model (correcting different effects for each other), jointly estimates animal effects and fixed effects (herds) but has Selection Index properties (Regression with " heritability ")

Background. A new coronavirus strain known as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) is responsible for the global pandemic that began in 2019 and continues to plague the planet. The disease's epidemiological features in Africa are different from those in other continents. The aim of this study is to establish the relationship that exists between COVID-19 patients' demographics, symptoms, comorbidities and the risk of COVID-19-related mortality in the Gambia between April 4, 2020 and March 31, 2021. Design. The researchers studied 3547 confirmed positive COVID-19 anonymized cases derived from the DHIS2 database in a retrospective cohort analysis. The factors analyzed include the demographics of the cases, their signs and symptoms, and their comorbidities. The main outcome of interest was death with COVID-19. Results. For the time period under consideration, 3547 anonymized positive COVID-19 events were analyzed. The fatality rate was 0.56%, with a median age of 60.5 (50-71) for those who died with COVID-19 and the pvalue < 0.001. Males are more likely to develop the disease and die from it (63.1% and 85%, respectively). Except for age and sex (both p < 0.05), all factors studied were considered to be statistically insignificantly correlated with the outcome. Cough (11.1%), fever (9.4%), and shortness of breath (4.3%) were the most common signs and symptoms identified by the cases. 4.62 % and 18.1 % of all confirmed positive COVID-19 cases, respectively, had one of the comorbidities and reported one of the COVID-19 signs and symptoms in TABLE 1. There was no statistically significant association between the signs and symptoms or the comorbidities and the outcome. CVD (2.7%), diabetes (1.5%), and ARDS (0.8%) and CLD (0.4%) were the most often identified comorbidities among the cases. Symptoms and comorbidities were reported more often by survivors than those who died with COVID-19. Age, shortness of breath, and diabetes all increase the risk of death with COVID-19, as per the multivariate logistic regression. In this analysis, however, only age was a significant predictor of mortality with COVID-19. Interpretation. The findings of our analysis are consistent with those of the Lusaka cohort, which reported that advanced age increased mortality with COVID-19, and that the most common comorbidities were CVD (hypertension) and diabetes, with a higher proportion of male COVID-19 cases. To better understand the characteristics of COVID-19 hospitalized cases in relation to death with COVID-19, length of hospitalization, and treatment, further exploratory data analysis is needed.

In my recent works, I propose a new theory of experience and chance, or the theory of certainties, which is a synthesis of two dual theories: Kolmogorov's theory of probabilities and a new theory of believabilities. The theory of experience and chance is based on axiomatics, adding to the Kolmogorov axiomatics of probability theory an axiom of co~event, a new concept defined as a pair of dual objects, one of which serves as a Kolmogorov event in probability space and the other - as an event in the dualistic believability space. One of my papers gives a theory of dual co~event-based means and examples of its use for processing
statistics of ``approving voting'' in elections and in forestry. In this paper, I will go into more detail in examples of processing the statistics
of ``approving voting'' in forestry, where a group of forestry experts is actually engaged in ``approving voting'' when they label the trees of the
forest, labelling those that according to their opinions must be felling. My goal is to show in these examples that the theory of experience and
chance is an effective tool for constructing co~evnts models of experts' behavior in different fields.

На 19.02.2016 г. Институтът по Древни цивилизации внесе в Министерството на Науката и Образованието (МОН) становище за промяна на концепцията за произхода на българите, прабългарите и древността на българската държава в учебниците по история, Вх.№ 09-62/19.02.2016 г. То подкрепя становището на Института по история на БАН по въпроса и предлага следните промени в съдържанието на учебниците за училищата:
1) Терминът “прабългари” да се замени с “древни българи”.
2) Произходът на древните българи е индоевропейски.
3) Титлата на българските владетели е „кан”.
4) Да се изучава Волжска България.
5) Да се разшири познанието за иранския древен свят.
6) Началото на българската държавност да бъде положено в 165 г.
7) Да се отмени периодизацията на първа, втора и трета българска държава, която не е уместна.
8.) В съвременния български език са запазени и се използват няколко хиляди думи от прабългарски произход, които се срещат също в индо - иранските езици. Повечето от тях погрешно са били обявени за турцизми.
9.) Древните българи са имали един от най-точните и най-древните календари. През 70-те години на XX-ти век той е бил предложен от ЮНЕСКО за световен календар, защото е изключително удобен за използване.

Относно дебата за замяната на термина “турско робство” Институтът по Древни цивилизации смята, че е от особено значение правилно да се употребява терминологията, използвана от авторите, които са били свидетели на тази епоха. Има неизброимо количество исторически писмени източници използващи масово термините “робство” и “иго”. Затова не е редно сега въпросният термин да бъде заменен в учебниците с други термини, независимо от каквито и да е съображения.

BACKGROUND::
QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.
METHODS::
Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.
RESULTS::
Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.
CONCLUSIONS::
These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potentially rich resource for the examination of the genetic variants and their covariates that affect complex phenotypes over time. We summarize eight contributions to the Genetic Analysis Workshop 18, which applied a diverse array of statistical genetic methods to analyze WGS data in combination with data from genome-wide association studies (GWAS) from up to four different time points on blood pressure phenotypes. The common goal of these analyses was to develop and apply appropriate methods that utilize longitudinal repeated measures to potentially increase the analytic efficiency of WGS and GWAS data. These diverse methods can be grouped into two categories, based on the way they model dependence structures: (1) linear mixed-effects (LME) models, where the random effect terms in the linear models are used to capture the dependence structures; and (2) variance-components models, where the dependence structures are constructed directly based on multiple components of variance-covariance matrices for the multivariate Gaussian responses. Despite the heterogeneous nature of these analytical methods, the group came to the following conclusions: (1) the use of repeat measurements can gain power to identify variants associated with the phenotype; (2) the inclusion of family data may correct genotyping errors and allow for more accurate detection of rare variants than using unrelated individuals only; and (3) fitting mixed-effects and variance-components models for longitudinal data presents computational challenges. The challenges and computational burden demanded by WGS data were addressed in the eight contributions.

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or-DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b ¼ 0:70 for cis-eQTLs andr b ¼ 0:78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.

Epigenomic data sets provide critical information about the dynamic role of chromatin states
in gene regulation, but a key question of how chromatin state segmentations vary under
different conditions across the genome has remained unaddressed. Here we present
ChromDiff, a group-wise chromatin state comparison method that generates an information theoretic representation of epigenomes and corrects for external covariate factors to better isolate relevant chromatin state changes. By applying ChromDiff to the 127 epigenomes from the Roadmap Epigenomics and ENCODE projects, we provide novel group-wise comparative analyses across sex, tissue type, state and developmental age. Remarkably, we find that distinct sets of epigenomic features are maximally discriminative for different group-wise comparisons, in each case revealing distinct enriched pathways, many of which do not show gene expression differences. Our methodology should be broadly applicable for epigenomic comparisons and provides a powerful new tool for studying chromatin state differences at the genome scale.

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved ...

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environment...

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central n...