Problems with Using Polygenic Scores to Select Embryos.

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle.

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.

Genome-wide association study identifies 74 loci associated with educational attainment.

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 environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Education can reduce health differences related to genetic risk of obesity.

This work investigates whether genetic makeup moderates the effects of education on health. Low statistical power and endogenous measures of environment have been obstacles to the credible estimation of such gene-by-environment interactions. We overcome these obstacles by combining a natural experiment that generated variation in secondary education with polygenic scores for a quarter-million individuals. The additional schooling affected body size, lung function, and blood pressure in middle age. The improvements in body size and lung function were larger for individuals with high genetic predisposition to obesity. As a result, education reduced the gap in unhealthy body size between those in the top and bottom terciles of genetic risk of obesity from 20 to 6 percentage points.

Outcomes of early versus late treatment of severe Class II high-angle patients.

INTRODUCTION: The aim of this work was to compare the skeletal and dental outcomes of 1- versus 2-phase treatment in Class II subjects with difficult-to-treat high-angle severe Class II malocclusions. METHODS: The sample of 120 cases was collected from the private offices of 3 experienced clinicians. The following selection criteria were used: (1) ANB ≥6°, (2) SN-GoGn ≥37° or mandibular plane to Frankfort horizontal plane ≥30°; and (3) overjet ≥6 mm. Patients were classified into either the early or the late treatment group according to dental age (early Tx: ≥5 primary teeth; late Tx: otherwise). Thirty-four angular, linear, and proportional measurements were determined for each patient. Statistical significance was assessed with the use of a 2-tailed t test, analysis of covariance test, and chi-square test. RESULTS: The results showed that early 2-phase treatment for severe Class II high-angle patients offered no skeletal anteroposterior advantages over late 1-phase treatment. Severe high-angle Class II patients also showed similar dental anteroposterior outcomes with the use of both approaches. Vertically there was a higher frequency of increased mandibular plane angles and extrusion of upper incisors and lower molars in the late treatment group. CONCLUSIONS: Early 2-phase treatment for severe Class II high-angle patients offered no skeletal or dental advantage over late 1-phase treatment.

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method.

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 in synaptic plasticity, the main cellular mechanism for learning and memory.

Evolution of esthetic considerations in orthodontics.

The importance of facial esthetics to the practice of orthodontics has its origins at the beginning of our specialty. In 1900, Edward H. Angle believed that an esthetic or a "harmonious" face required a full complement of teeth, but many who came after him questioned this notion. In the 1930s, the development of cephalometrics laid the foundation for studying growth and development, treatment effects, facial forms, and esthetics. By the 1950s, the importance of diagnosing and planning treatment for an esthetic result was established, but the measurement of soft tissue variables was lacking, and this became an important area of research. In the 1970s, researchers were looking at the stability of hard tissue changes over time, and they were also interested in how the soft tissues change with age. Although the early studies of esthetics in orthodontic treatment focused on how clinicians viewed their patients, changing demographics and cultural attitudes led researchers to look more seriously at consumer preferences and the public's attitudes. Their findings--that consumers preferred fuller lips--led to a swing back toward nonextraction treatment. Expansion appliances and molar distalization techniques became popular, and surgical procedures to obtain more ideal esthetic results became more common. Since the 1990s, advances in computers and technology have allowed us to study, predict, and produce esthetic results previously thought unattainable. Today, more so than at any other time in our specialty, we have the ability to provide esthetic results to our patients.

Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries.

We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.

Distinct and shared genetic architectures of gestational diabetes mellitus and type 2 diabetes.

Gestational diabetes mellitus (GDM) is a common metabolic disorder affecting more than 16 million pregnancies annually worldwide1,2. GDM is related to an increased lifetime risk of type 2 diabetes (T2D)1-3, with over a third of women developing T2D within 15 years of their GDM diagnosis. The diseases are hypothesized to share a genetic predisposition1-7, but few studies have sought to uncover the genetic underpinnings of GDM. Most studies have evaluated the impact of T2D loci only8-10, and the three prior genome-wide association studies of GDM11-13 have identified only five loci, limiting the power to assess to what extent variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen study and identified 13 GDM-associated loci, including nine new loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into the following two distinct categories: one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis and placental expression.

DISTRIBUTIONAL EFFECTS OF EDUCATION ON HEALTH.

This paper studies distributional effects of education on health. In 1972, England, Scotland, and Wales raised their minimum school-leaving age from 15 to 16 for students born after 9/1/1957. Using a regression discontinuity design and objective health measures for 129,000 individuals, we find that education reduced body size and increased blood pressure in middle age. The reduction in body size was concentrated at the upper tail of the distribution with an 8 percentage point reduction in obesity. The increase in blood pressure was concentrated at the lower tail of the distribution with no effect on stage 2 hypertension.

Public views on polygenic screening of embryos.

Understanding moral acceptability and willingness to use is crucial for informing policy.

Wrestling with Public Input on an Ethical Analysis of Scientific Research.

Bioethicists frequently call for empirical researchers to engage participants and community members in their research, but don't themselves typically engage community members in their normative research. In this article, we describe an effort to include members of the public in normative discussions about the risks, potential benefits, and ethical responsibilities of social and behavioral genomics (SBG) research. We reflect on what might-and might not- be gained from engaging the public in normative scholarship and on lessons learned about public perspectives on the risks and potential benefits of SBG research and the responsible conduct and communication of such research. We also provide procedural lessons for others in bioethics who are interested in engaging members of the public in their research.

A General Approach to Adjusting Genetic Studies for Assortative Mating.

The effects of assortative mating (AM) on estimates from genetic studies has been receiving increasing attention in recent years. We extend existing AM theory to more general models of sorting and conclude that correct theory-based AM adjustments require knowledge of complicated, unknown historical sorting patterns. We propose a simple, general-purpose approach using polygenic indexes (PGIs). Our approach can estimate the fraction of genetic variance and genetic correlation that is driven by AM. Our approach is less effective when applied to Mendelian randomization (MR) studies for two reasons: AM can induce a form of selection bias in MR studies that remains after our adjustment; and, in the MR context, the adjustment is particularly sensitive to PGI estimation error. Using data from the UK Biobank, we find that AM inflates genetic correlation estimates between health traits and education by 14% on average. Our results suggest caution in interpreting genetic correlations or MR estimates for traits subject to AM.

Polygenic prediction across populations is influenced by ancestry, genetic architecture, and methodology.

Polygenic risk scores (PRSs) developed from multi-ancestry genome-wide association studies (GWASs), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulti compared with PRSs constructed from single-ancestry GWASs (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmulti overall outperformed PRSsingle in understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Furthermore, integrating PRSs based on local ancestry-informed GWASs and large-scale, European-based PRSs improved predictive performance in understudied African populations, especially for less polygenic traits with large-effect ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRSs from multiple studies.

Wrestling with Social and Behavioral Genomics: Risks, Potential Benefits, and Ethical Responsibility.

In this consensus report by a diverse group of academics who conduct and/or are concerned about social and behavioral genomics (SBG) research, the authors recount the often-ugly history of scientific attempts to understand the genetic contributions to human behaviors and social outcomes. They then describe what the current science-including genomewide association studies and polygenic indexes-can and cannot tell us, as well as its risks and potential benefits. They conclude with a discussion of responsible behavior in the context of SBG research. SBG research that compares individuals within a group according to a "sensitive" phenotype requires extra attention to responsible conduct and to responsible communication about the research and its findings. SBG research (1) on sensitive phenotypes that (2) compares two or more groups defined by (a) race, (b) ethnicity, or (c) genetic ancestry (where genetic ancestry could easily be misunderstood as race or ethnicity) requires a compelling justification to be conducted, funded, or published. All authors agree that this justification at least requires a convincing argument that a study's design could yield scientifically valid results; some authors would additionally require the study to have a socially favorable risk-benefit profile.