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Over the last decade the availability of SNP-trait associations from genome-wide association studies has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification. In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method’s performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes. Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias., Author summary Uncovering causal mechanisms between risk factors and disease is challenging with observational data because of unobserved confounding. Mendelian randomization offers a potential solution by replacing an individual’s observed risk factor data with an unconfounded genetic proxy measure. Over the last decade an array of methods for performing Mendelian randomization studies (MR) using publicly available summary statistics gleaned from two separate genome-wide association studies. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well-developed summary data methods to individual level data. In this paper we describe a general procedure for optimally applying any summary data MR method using individual level data from one cohort study. Our approach may at first seem nonsensical: we create summary statistics that are intentionally biased by confounding. This bias can, however, be very accurately estimated, and the estimate then used to correct the results of a standard observational analysis. We apply our new way of performing an MR analysis to data from UK Biobank to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes.

Facial attractiveness is a complex human trait of great interest in both academia and industry. Literature on sociological and phenotypic factors associated with facial attractiveness is rich, but its genetic basis is poorly understood. In this paper, we conducted a genome-wide association study to discover genetic variants associated with facial attractiveness using 4,383 samples in the Wisconsin Longitudinal Study. We identified two genome-wide significant loci, highlighted a handful of candidate genes, and demonstrated enrichment for heritability in human tissues involved in reproduction and hormone synthesis. Additionally, facial attractiveness showed strong and negative genetic correlations with BMI in females and with blood lipids in males. Our analysis also suggested sex-specific selection pressure on variants associated with lower male attractiveness. These results revealed sex-specific genetic architecture of facial attractiveness and provided fundamental new insights into its genetic basis., Author summary Facial attractiveness is a complex human trait well integrated into people’s daily life experience with profound influence on human behavior. Despite being widely studied in sociology, psychology, and related fields, its genetic basis remains poorly understood. Using carefully-measured facial attractiveness and dense genotyping data from the Wisconsin Longitudinal Study, we identified novel genes for facial attractiveness, assessed the selection signature, and dissected the shared genetic architecture between facial attractiveness and various human traits. Interestingly, sex-specific genetic architecture of facial attractiveness was a recurrent pattern observed in almost all our analyses. Our results provided new insights into the genetic basis of facial attractiveness and have broad implications for the complex relationships between attractiveness and various human traits.

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis., Author Summary There is a great deal of evidence that genes influence facial appearance. This is perhaps most apparent when we look at our own families, since we are more likely to share facial features in common with our close relatives than with unrelated individuals. Nevertheless, little is known about how variation in specific regions of the genome relates to the kinds of distinguishing facial characteristics that give us our unique identities, e.g., the size and shape of our nose or how far apart our eyes are spaced. In this paper, we investigate this question by examining the association between genetic variants across the whole genome and a set of measurements designed to capture key aspects of facial form. We found evidence of genetic associations involving measures of eye, nose, and facial breadth. In several cases, implicated regions contained genes known to play roles in embryonic face formation or in syndromes in which the face is affected. Our ability to connect specific genetic variants to ubiquitous facial traits can inform our understanding of normal and abnormal craniofacial development, provide potential predictive models of evolutionary changes in human facial features, and improve our ability to create forensic facial reconstructions from DNA.

Results from Genome-Wide Association Studies (GWAS) have shown that complex diseases are often affected by many genetic variants with small or moderate effects. Identifications of these risk variants remain a very challenging problem. There is a need to develop more powerful statistical methods to leverage available information to improve upon traditional approaches that focus on a single GWAS dataset without incorporating additional data. In this paper, we propose a novel statistical approach, GPA (Genetic analysis incorporating Pleiotropy and Annotation), to increase statistical power to identify risk variants through joint analysis of multiple GWAS data sets and annotation information because: (1) accumulating evidence suggests that different complex diseases share common risk bases, i.e., pleiotropy; and (2) functionally annotated variants have been consistently demonstrated to be enriched among GWAS hits. GPA can integrate multiple GWAS datasets and functional annotations to seek association signals, and it can also perform hypothesis testing to test the presence of pleiotropy and enrichment of functional annotation. Statistical inference of the model parameters and SNP ranking is achieved through an EM algorithm that can handle genome-wide markers efficiently. When we applied GPA to jointly analyze five psychiatric disorders with annotation information, not only did GPA identify many weak signals missed by the traditional single phenotype analysis, but it also revealed relationships in the genetic architecture of these disorders. Using our hypothesis testing framework, statistically significant pleiotropic effects were detected among these psychiatric disorders, and the markers annotated in the central nervous system genes and eQTLs from the Genotype-Tissue Expression (GTEx) database were significantly enriched. We also applied GPA to a bladder cancer GWAS data set with the ENCODE DNase-seq data from 125 cell lines. GPA was able to detect cell lines that are biologically more relevant to bladder cancer. The R implementation of GPA is currently available at http://dongjunchung.github.io/GPA/., Author Summary In the past 10 years, many genome wide association studies (GWAS) have been conducted to identify the genetic bases of complex human traits. As of January, 2014, more than 12,000 single-nucleotide polymorphisms (SNPs) have been reported to be significantly associated with at least one complex trait/disease. On one hand, about 85% of identified risk variants are located in non-coding regions, which motivates a systematic understanding of the function of non-coding variants in regulatory elements in the human genome. On the other hand, complex diseases are often affected by many genetic variants with small or moderate effects. To address these issues, we propose a statistical approach, GPA, to integrating information from multiple GWAS datasets and functional annotation. Notably, our approach only requires marker-wise p-values as input, making it especially useful when only summary statistics, instead of the full genotype and phenotype data, are available. We applied GPA to analyze GWAS datasets of five psychiatric disorders and bladder cancer, where the central nervous system genes, eQTLs from the Genotype-Tissue Expression (GTEx), and the ENCODE DNase-seq data from 125 cell lines were used as functional annotation. The analysis results suggest that GPA is an effective method for integrative data analysis in the post-GWAS era.