Madole & Harden's assertion that the effects derived from within-family genome-wide association studies (GWASs) and from randomized controlled trials (RCTs) are equivalent is misleading. GWASs are substantially more “non-unitary, non-uniform, and non-explanatory” than RCTs. While the within-family GWAS bring us closer to identifying genetic causes, whether it will change behavioral genetics into a causal science is an open question.

We address Turkheimer’s argument that genome-wide association studies of behaviors and psychiatric traits will fail to produce coherent explanations. We distinguish two major sources of potential i...

Polygenic scores (PGSs) have several limitations. They are confounded with environmental effects on behavior and cannot be used to study how mutations affect brain function and behavior. For this, mutations with large effects, which often arise in only one geographical population are needed. Genome-wide association studies (GWASs), commonly used for identifying mutations, have difficulty detecting these mutations. A strategy that overcomes this challenge is discussed.

In this article we examine the “phenotype” concept in light of recent technological advances in Genome-Wide Association Studies . By observing the technology and its presuppositions, we put forward the thesis that at least in this case genotype and phenotype are effectively coidentifled one by means of the other. We suggest that the coidentiflcation of genotype-phenotype couples in expression-based GWAS also indicates a conceptual dependence, which we call “co-deñnition.” We note that viewing these terms as codeflned runs (...) against possible expectations, viz., that genotypes and phenotypes could ultimately be expressed independently from one another. In addition, the co-definition of genotypes and phenotypes in this context emphasizes the correlative character of both genotypes and phenotypes in GWAS. (shrink)

Genome-wide association studies raise important ethical and regulatory issues. This is particularly true of the current move toward broad sharing of genomic and phenotypic data. Our survey study examined the opinions of professionals involved in human subjects protection regarding genetic research review. The majority indicated that it is important for their institutional review board to offer guidance about developing and using a data repository or biobank that includes genetic data, and also about sharing this data with (...) other investigators. Only one-third of respondents reported that the National Institutes of Health policy regarding data sharing among researchers in genome-wide association studies is clear. Another third answered that they did not know whether this policy is clear. Findings from this study suggest a need for increased education for IRB professionals regarding the existing data sharing policy, collaboration among IRB professionals and researchers to define best practices, and further empirical research into prospective research participants’ information needs and preferences in the context of wide data sharing. (shrink)

Higher states of consciousness in which the human mind can transcend the boundaries of logic and reason are envisioned as natural to the experience and potential growth of every human being. So far they have been mostly monitored by electrophysiological methods. In this study we were particularly interested in discovering the molecular transcriptional basis of higher states of consciousness. In addition to phenomenological reports of meditators who participated in this study the generated higher states of consciousness were also (...) EEG recorded. We assessed the whole genome gene expression analysis of long-term meditators in four separate trials and detected significant differential gene expression in association with higher states of consciousness. The number of differently expressed genes as well as high proportion of genes themselves differed between meditators. Despite this, gene ontology enrichment analysis found significant biological and molecular processes shared among meditators’ higher state of consciousness. (shrink)

Long noncoding RNAs have been described in cell lines and various whole tissues, but lncRNA analysis of development in vivo is limited. Here, we comprehensively analyze lncRNA expression for the adult mouse subventricular zone neural stem cell lineage. We utilize complementary genome-wide techniques including RNA-seq, RNA CaptureSeq, and ChIP-seq to associate specific lncRNAs with neural cell types, developmental processes, and human disease states. By integrating data from chromatin state maps, custom microarrays, and FACS purification of the subventricular zone (...) lineage, we stringently identify lncRNAs with potential roles in adult neurogenesis. shRNA-mediated knockdown of two such lncRNAs, Six3os and Dlx1as, indicate roles for lncRNAs in the glial-neuronal lineage specification of multipotent adult stem cells. Our data and workflow thus provide a uniquely coherent in vivo lncRNA analysis and form the foundation of a user-friendly online resource for the study of lncRNAs in development and disease. © 2013 Elsevier Inc. (shrink)

Recent years have witnessed an explosion of the single-cell biochemical toolbox including chromosome conformation capture -based methods that provide novel insights into chromatin spatial organization in individual cells. The observations made with these techniques revealed that topologically associating domains emerge from cell population averages and do not exist as static structures in individual cells. Stochastic nature of the genome folding is likely to be biologically relevant and may reflect the ability of chromatin fibers to adopt a number of alternative (...) configurations, some of which could be transiently stabilized and serve regulatory purposes. Single-cell Hi-C approaches provide an opportunity to analyze chromatin folding in rare cell types such as stem cells, tumor progenitors, oocytes, and totipotent cells, contributing to a deeper understanding of basic mechanisms in development and disease. Here, we review key findings of single-cell Hi-C and discuss possible biological reasons and consequences of the inferred dynamic chromatin spatial organization. Single-cell Hi-C expands the molecular biology toolbox for studies of chromatin structure in individual cells. This technique allows one to analyze cell-to-cell variability in TAD and loop structure, and to capture chromosome conformation in rare cell types such as oocytes, totipotent cells, and tumor progenitors. (shrink)

BackgroundObtaining informed consent for participation in genomic research in low-income settings presents specific ethical issues requiring attention. These include the challenges that arise when providing information about unfamiliar and technical research methods, the implications of complicated infrastructure and data sharing requirements, and the potential consequences of future research with samples and data. This study investigated researchers’ and participants’ parents’ experiences of a consent process and understandings of a genome-wide association study of malaria involving children aged (...) five and under in Mali. It aimed to inform best practices in recruiting participants into genomic research.MethodsA qualitative rapid ethical assessment was undertaken. Fifty-five semi-structured interviews were conducted with the parents of research participants. An additional nine semi-structured interviews were conducted with senior research scientists, research assistants and with a member of an ethics committee. A focus group with five parents of research participants and direct observations of four consent processes were also conducted. French and translated English transcripts were descriptively and thematically coded using OpenCode software.ResultsParticipants’ parents in the MalariaGEN study had differing understandings of the causes of malaria, the rationale for collecting blood samples, the purposes of the study and the kinds of information the study would generate. Genomic aspects of the research, including the gene/environment interaction underlying susceptibility or resistance to severe malaria, proved particularly challenging to explain and understand.ConclusionsThis study identifies a number of areas to be addressed in the design of consent processes for genomic research, some of which require careful ethical analysis. These include determining how much information should be provided about differing aspects of the research and how best to promote understandings of genomic research. We conclude that it is important to build capacity in the design and conduct of effective and appropriate consent processes for genomic research in low and middle-income settings. Additionally, consideration should be given to the role of review committees and community consultation activities in protecting the interests of participants in genomic research. (shrink)

BackgroundGenome-wide association studies (GWAS) provide a powerful means of identifying genetic variants that play a role in common diseases. Such studies present important ethical challenges. An increasing number of GWAS is taking place in lower income countries and there is a pressing need to identify the particular ethical challenges arising in such contexts. In this paper, we draw upon the experiences of the MalariaGEN Consortium to identify specific ethical issues raised by such research in Africa, Asia and Oceania.DiscussionWe (...) explore ethical issues in three key areas: protecting the interests of research participants, regulation of international collaborative genomics research and protecting the interests of scientists in low income countries. With regard to participants, important challenges are raised about community consultation and consent. Genomics research raises ethical and governance issues about sample export and ownership, about the use of archived samples and about the complexity of reviewing such large international projects. In the context of protecting the interests of researchers in low income countries, we discuss aspects of data sharing and capacity building that need to be considered for sustainable and mutually beneficial collaborations.SummaryMany ethical issues are raised when genomics research is conducted on populations that are characterised by lower average income and literacy levels, such as the populations included in MalariaGEN. It is important that such issues are appropriately addressed in such research. Our experience suggests that the ethical issues in genomics research can best be identified, analysed and addressed where ethics is embedded in the design and implementation of such research projects. (shrink)

Circadian rhythm abnormalities in bipolar disorder have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies. At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network (...) at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD. Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies. (shrink)

Behaving presents an overview of the recent history and methodology of behavioral genetics and psychiatric genetics, informed by a philosophical perspective. Kenneth F. Schaffner addresses a wide range of issues, including genetic reductionism and determinism, "free will," and quantitative and molecular genetics. The latter covers newer genome-wide association studies that have produced a paradigm shift in the subject, and generated the problem of "missing heritability." Schaffner also presents cases involving pro and con arguments for genetic testing (...) for IQ and for Attention Deficit Hyperactivity Disorder. Schaffner examines the nature-nurture controversy and Developmental Systems Theory using C. elegans or "worm" studies as a test case, concluding that genes are special and provide powerful tools, including "deep homology," for investigating behavior. He offers a novel account of biological knowledge emphasizing the importance of models, mechanisms, pathways, and networks, which clarifies how partial reductions provide explanations of traits and disorders. The book also includes examinations of personality genetics and of schizophrenia and its etiology, alongside interviews with prominent researchers in the area, and discusses debates about psychosis that led to changes in the DSM-5 in 2013.Schaffner concludes by discussing additional philosophical implications of the genetic analyses in the book, some major worries about "free will," and arguments pro and con about why genes and DNA are so special. Though genes are special, newer perspectives presented in this book will be needed for progress in behavioral genetics- perspectives that situate genes in complex multilevel prototypic pathways and networks. With a mix of optimism and pessimism about the state of the field and the subject, Schaffner's book will be of interest to scholars in the history and philosophy of science, medicine, and psychiatry. (shrink)

The everyday harms of structural racism and discrimination, perpetuated through institutions, laws, policies, and practices, constitute social determinants of health, but measures that account for their debilitating effects are largely missing in genetic studies of complex diseases. Drawing on insights from the social sciences and public health, we propose critical methodologies for incorporating tools that measure structural racism and discrimination within genetic analyses. We illustrate how including these measures may strengthen the accuracy and utility of findings for diverse communities, clarify (...) elusive relationships between genetics and environment in a racialized society, and support greater equity within genomics and precision health research. This approach may also support efforts to build and sustain vital partnerships with communities and with other fields of research inquiry, centering community expertise and lived experiences and drawing on valuable knowledge from practitioners in the social sciences and public health to innovate biomedical and genomic study designs aimed at community health priorities. (shrink)

We argue that Madole & Harden's distinction between shallow versus deep genetic causes can bring some clarity to causal claims arising from genome-wide association studies (GWASs). However, the authors argue that GWAS only finds shallow genetic causes, making GWAS commensurate with the environmental studies they hope to supplant. We also assess whether their distinction applies best to explanations or causes.

The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and (...) even contradictory findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically. (shrink)

Genome-wide association studies of human complex traits have provided us with new estimates of heritability. These estimates foreground the question of genetic causation. After having presen...

The use of genome-wide association studies in medical research and the increased ability to share data give a new twist to some of the perennial ethical issues associated with genomic research. GWAS create particular challenges because they produce fine, detailed, genotype information at high resolution, and the results of more focused studies can potentially be used to determine genetic variation for a wide range of conditions and traits. The information from a GWA scan is derived from (...) DNA that is a powerful personal identifier, and can provide information not just on the individual, but also on the individual's relatives, related groups, and populations. Furthermore, it creates large amounts of individual-specific digital information that is easy to share across international borders. This paper provides an overview of some of the key ethical issues around GWAS: consent, feedback of results, privacy, and the governance of research. Many of the questions that lie ahead of us in terms of the next generation sequencing methods will have been foreshadowed by GWAS and the debates around ethical and policy issues that these have created. (shrink)

Recent research with human embryos, in different parts of the world, has sparked a new debate on the ethics of genetic human enhancement. This debate, however, has mainly focused on gene-editing technologies, especially CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). Less attention has been given to the prospect of pursuing genetic human enhancement by means of IVF (In Vitro Fertilisation) in conjunction with in vitro gametogenesis, genome-wide association studies, and embryo selection. This article examines the different ethical (...) implications of the quest for cognitive enhancement by means of gene-editing on the one hand, and embryo selection on the other. The article focuses on the ethics of cognitive enhancement by means of embryo selection, as this technology is more likely to become commercially available before cognitive enhancement by means of gene-editing. This article argues that the philosophical debate on the ethics of enhancement should take into consideration public attitudes to research on human genomics and human enhancement technologies. The article discusses, then, some of the recent findings of the SIENNA Project, which in 2019 conducted a survey on public attitudes to human genomics and human enhancement technologies in 11 countries (France, Germany, Greece, the Netherlands, Poland, Spain, Sweden, Brazil, South Africa, South Korea, and United States). (shrink)

Heterogeneous treatment effects represent a major issue for medicine as they undermine reliable inference and clinical decision-making. To overcome the issue, the current vision of precision and personalized medicine acknowledges the need to control individual variability in response to treatment. In this paper, we argue that gene-treatment-environment interactions (G × T × E) undermine inferences about individual treatment effects from the results of both genomics-based methodologies—such as genome-wide association studies (GWAS) and genome-wide interaction studies (GWIS)—and (...) randomized controlled trials (RCTs). Then, we argue that N-of-1 trials can be a solution to overcome difficulties in handling individual variability in treatment response. Although this type of trial has been suggested as a promising strategy to assess individual treatment effects, it nonetheless has limitations that limit its use in everyday clinical practice. We analyze the existing variability within the designs of N-of-1 trials in terms of a continuum where each design prioritizes epistemic and pragmatic considerations. We then support wider use of the designs located at the pragmatic end of the explanatory-pragmatic continuum. (shrink)

Madole & Harden argue that the Mendelian reshuffling of genes and genomes is analogous to randomised controlled trials. We are not convinced by their arguments. First, their recipe for meeting the demands on randomised experiments is inherently inconsistent. Second, disequilibrium across chromosomes conflicts with their assumption of statistical independence. Third, the genome-wide association study (GWAS) method has many pitfalls, including low repeatability.

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and (...) 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

Background: Seeking consent for genetic and genomic research can be challenging, particularly in populations with low literacy levels, and in emergency situations. All of these factors were relevant to the MalariaGEN study of genetic factors influencing immune responses to malaria in northern rural Ghana. This study sought to identify issues arising in practice during the enrolment of paediatric cases with severe malaria and matched healthy controls into the MalariaGEN study. Methods: The study used a rapid assessment (...) incorporating multiple qualitative methods including in depth interviews, focus group discussions and observations of consent processes. Differences between verbal information provided during community engagement processes, and consent processes during the enrolment of cases and controls were identified, as well as the factors influencing the tailoring of such information. Results: MalariaGEN participants and field staff seeking consent were generally satisfied with their understanding of the project and were familiar with aspects of the study relating to malaria. Some genetic aspects of the study were also well understood. Participants and staff seeking consent were less aware of the methodologies employed during genomic research and their implications, such as the breadth of data generated and the potential for future secondary research.Moreover, trust in and previous experience with the Navrongo Health Research Centre which was conducting the research influenced beliefs about the benefits of participating in the MalariaGEN study and subsequent decision-making about research participation. Conclusions: It is important to recognise that some aspects of complex genomic research may be of less interest to and less well understood by research participants and that such gaps in understanding may not be entirely addressed by best practice in the design and conduct of consent processes. In such circumstances consideration needs to be given to additional protections for participants that may need to be implemented in such research, and how best to provide such protections.Capacity building for research ethics committees with limited familiarity with genetic and genomic research, and appropriate engagement with communities to elicit opinions of the ethical issues arising and acceptability of downstream uses of genome wide association data are likely to be important. (shrink)

Over the past two decades there has been a rapid expansion in our understanding of how human genetic variability impacts susceptibility and severity of disease. Through applications of genome-wide association studies, genome and exome sequencing, researchers have made thousands of discoveries of genetic variants that impact risk of common and rare disorders affecting millions of people. Although these techniques have been primarily applied to highly prevalent chronic disorders such as diabetes1 and cardiovascular disease2, infectious diseases have (...) proven to not be immune to genome-wide association, with studies of Tuberculosis3, HIV4 and SARS-CoV25, to name but a few, identifying host susceptibility loci across the genome. Unlike non-communicable diseases, infectious diseases have the unique element of impacting not only the affected the host, but those who may be most vulnerable to acquiring the infection. Thus, genetic variants that impact one individual’s susceptibility to and severity of an infection may also have broader implications to public health, as was brought into keen focus during the COVID-19 pandemic. Therefore, as we begin to apply the knowledge gained from genomic studies in the clinic or into policy, there are unique ethical, legal, and social implications (ELSI) at the intersection of infectious diseases and human genomics. In this issue of the Journal of Law, Medicine and Ethics, Jose et al attempt to address this need by proposing a research agenda for ELSI studies at what they term the “blurred boundaries” of infectious and genetic diseases.6. (shrink)

The development of improved methods for genome‐wide association studies (GWAS) for genetics of quantitative traits has been an active area of research during the last 25 years. This activity initially started with the use of mixed linear model (MLM), which was variously modified. During the last decade, however, with the availability of high throughput next generation sequencing (NGS) technology, development and use of pangenomes and novel markers including structural variations (SVs) and k‐mers for GWAS has taken over (...) as a new thrust area of research. Pangenomes and SVs are now available in humans, livestock, and a number of plant species, so that these resources along with k‐mers are being used in GWAS for exploring additional genetic variation that was hitherto not available for analysis. These developments have resulted in significant improvement in GWAS methodology for detection of marker‐trait associations (MTAs) that are relevant to human healthcare and crop improvement. (shrink)

Seeking consent for genetic and genomic research can be challenging, particularly in populations with low literacy levels, and in emergency situations. All of these factors were relevant to the MalariaGEN study of genetic factors influencing immune responses to malaria in northern rural Ghana. This study sought to identify issues arising in practice during the enrolment of paediatric cases with severe malaria and matched healthy controls into the MalariaGEN study.

In lieu of an abstract, here is a brief excerpt of the content:The Post-Genomic RevolutionA Paradigm Shift for Biopsychosocial SystemsClaude Robert Cloninger, MD, PhD (bio)The pstchologist Danielle Dick and psychiatrist Kenneth Kendler (DK) began an ongoing study in 2011 called Spit for Science (S4S) in which they obtained saliva as a peripheral source of DNA along with assessment of detailed self-report information on alcohol and other substance use, selected personality traits, and psychosocial history about the students entering a large (...) university (Dick et al., 2014). They hoped to identify the genes underlying the heritability of alcohol use and related behaviors to inform students about their individual risk, and thereby to promote increased self-awareness and health. The students were highly cooperative volunteers, and many peer-reviewed research papers have been published from these data.Eric Turkheimer, a psychologist who studies how genes and environments shape the development of human behavior (Harden et al., 2007; Loehlin et al., 2009; Turkheimer et al., 2003), reviewed all the resulting publications coming from S4S along with coauthor Sarah Greer (Turkheimer & Greer, 2024). Turkheimer and Greer (TG) were surprised to find the study has failed to identify any genes that have substantial (“nontrivial”) effects on reported levels of consumption or problems related to their use of alcohol or other substances, except for a variant of the gene for aldehyde dehydrogenase (ALDH2), which was already known to cause many people of Asian descent to flush when they drink alcohol. TG state that, “Again and again, the results of S4S investigations demonstrated tiny, and frequently null, contributions of genetics to differences in drinking and related behaviors among college students. GWAS [genome-wide association studies] revealed practically no genome-wide significant SNPs [single nucleotide polymorphisms], and the SNPs identified at less stringent levels of significance were never mentioned more than once” (Turkheimer & Greer, 2024).TG concluded that the design, execution, psychometric measures, and analysis of the data were excellent. However, they also discuss facts that raise doubts about the adequacy of the design and methods. Namely, it is an inconvenient fact, [End Page 429] but widely known, that approaches to GWAS that are frequently used in psychiatric genetics require huge samples (often hundreds of thousands) to detect statistically significant genes because the observed effects have consistently been weak whenever genes are assumed to act independently, as did DK. Consequently, polygenic risk scores are weak and inconsistent predictors of behavioral phenotypes (Zwir et al., 2020c). Nevertheless, TG fault DK and their coauthors for an overemphasis on statistical significance in large samples rather than prominently reporting that the observed effect sizes of genes were only weakly and inconsistently associated with any measured features of substance use.TG report that they were surprised by the weak and inconsistent findings from genetic variants from this GWAS because they knew that twin and family studies (i.e., what they call “genetics at altitude”) have previously found strong and consistent evidence of the heritability of phenotypes like those measured by DK. For example, in my own research with adoptees separated from their biological parents at an early age and reared by adoptive parents, the risk of alcohol abuse in adoptees was strongly predicted by alcohol abuse and related behaviors in their biological, but not adoptive, parents (Bohman et al., 1981; Cloninger et al., 1981; Sigvardsson et al., 1996) and by their childhood personality, particularly novelty seeking, when the children were followed into young adulthood (Cloninger, 1987; Cloninger et al., 1988). However, it is well-known that the methods used by DK for GWAS consistently fail to detect most of the heritable variance for behavioral phenotypes estimated in twin studies, which include much variability from complex patterns of gene–gene interaction (Table 1) (Cloninger & Zwir, 2022). This consistent observation in GWAS studies that assume genes act independently is called the missing or hidden heritability problem.Nevertheless, DK expressed optimism in 2011 that genome-wide measurement of genetic variants would identify genetic markers to predict risk of alcohol-related phenotypes in college students. They do so because they assume that all the information about heritable processes can be extracted from genome-wise scans of SNPS. The heritable phenotypes of interest in S4S included patterns of use of alcohol and other recreational... (shrink)

Transcription factor binding sites (TFBSs) on the DNA are generally accepted as the key nodes of gene control. However, the multitudes of TFBSs identified in genome‐wide studies, some of them seemingly unconstrained in evolution, have prompted the view that in many cases TF binding may serve no biological function. Yet, insights from transcriptional biochemistry, population genetics and functional genomics suggest that rather than segregating into ‘functional’ or ‘non‐functional’, TFBS inputs to their target genes may be generally cumulative, with (...) varying degrees of potency and redundancy. As TFBS redundancy can be diminished by mutations and environmental stress, some of the apparently ‘spurious’ sites may turn out to be important for maintaining adequate transcriptional regulation under these conditions. This has significant implications for interpreting the phenotypic effects of TFBS mutations, particularly in the context of genome‐wide association studies for complex traits. (shrink)

Heritability estimates obtained from genome-wide association studies are much lower than those of traditional quantitative methods. This phenomenon has been called the “missing heritability problem.” By analyzing and comparing GWAS and traditional quantitative methods, we first show that the estimates obtained from the latter involve some terms other than additive genetic variance, while the estimates from the former do not. Second, GWAS, when used to estimate heritability, do not take into account additive epigenetic factors transmitted across generations, (...) while traditional quantitative methods do. Given these two points we show that the missing heritability problem can largely be dissolved. (shrink)

It is now well-appreciated by philosophers that contemporary large-scale ‘-omics’ studies in biology stand in non-trivial relationships to more orthodox hypothesis-driven approaches. These relationships have been clarified by Ratti (2015); however, there remains much more to be said regarding how an important field of genomics cited in that work—‘genome-wide association studies’ (GWAS)—fits into this framework. In the present article, we propose a revision to Ratti’s framework more suited to studies such as GWAS. In the process of doing (...) so, we introduce to the philosophical literature novel exploratory experiments in (phospho)proteomics, and demonstrate how these experiments interplay with the above considerations. (shrink)

Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, (...) modelled as a parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy. (shrink)

The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome‐wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non‐coding part of the genome, preferentially within enhancers. Enhancers are distal cis‐regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome‐wide maps for histone marks (e.g., (...) H3K27ac), chromatin accessibility and transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease‐associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease‐associated non‐coding genetic variants might be preferentially (or even only) manifested under environmental stress. (shrink)

DNA copy number variation (CNV) represents a considerable source of human genetic diversity. Recently,1 a global map of copy number variation in the human genome has been drawn up which reveals not only the ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than 20 Mb and it is likely that the full extent of CNV still remains to be discovered. Nearly 3000 genes are associated with CNV. This high degree (...) of variability with regard to gene copy number between two individuals challenges definitions of normality. Many CNVs are located in regions of complex genomic structure and this currently limits the extent to which these variants can be genotyped by using tagging SNPs. However, some CNVs are already amenable to genome‐wide association studies so that their influence on human phenotypic diversity and disease susceptibility may soon be determined. BioEssays 29:311–313, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Uchiyama et al. productively discuss how culture can influence genetic heritability and, by modifying environmental conditions, limit the generalizability of genome-wide association studies (GWASs). Here, we supplement their account by highlighting how recent changes in culture and institutions in industrialized, westernized societies – such as increased female workforce participation – may have increased assortative mating. This alters the distribution of genotypes themselves, increasing heritability and phenotypic variance, and may be detectable using the latest methods.

Understanding the functional mechanisms underlying genetic signals associated with complex traits and common diseases, such as cancer, diabetes and Alzheimer's disease, is a formidable challenge. Many genetic signals discovered through genome‐wide association studies map to non‐protein coding sequences, where their molecular consequences are difficult to evaluate. This article summarizes concepts for the systematic interpretation of non‐coding genetic signals using genome annotation data sets in different cellular systems. We outline strategies for the global analysis of multiple (...) class='Hi'>association intervals and the in‐depth molecular investigation of individual intervals. We highlight experimental techniques to validate candidate (potential causal) regulatory variants, with a focus on novel genome‐editing techniques including CRISPR/Cas9. These approaches are also applicable to low‐frequency and rare variants, which have become increasingly important in genomic studies of complex traits and diseases. There is a pressing need to translate genetic signals into biological mechanisms, leading to prognostic, diagnostic and therapeutic advances. (shrink)

The promise of personalized medicine and the quest for a greater understanding of the genetic basis of disease has transformed the research enterprise. The Director of the National Institutes of Health, Elias A. Zerhouni, M.D., recently predicted “that comprehensive, genomics- based health care will become the norm, with individualized preventive medicine and early detection of illnesses.” This excitement about the potential scientific and clinical advances that may come from genomics- based research has led several NIH institutions to launch initiatives for (...) genome-wide association studies, calling on researchers and institutions to utilize the new DNA analysis technologies to study the genetic variation between individuals with a particular illness and healthy controls. (shrink)

This paper, addressed to both philosophers of science and stem cell biologists, aims to reduce the obscurity of and disagreements over the nature of stemness. The two most prominent current theories of stemness—the entity theory and the state theory—are both biologically and philosophically unsatisfactory. Improved versions of these theories are likely to converge. Philosophers of science can perform a much needed service in clarifying and formulating ways of testing entity and state theories of stemness. To do so, however, philosophers should (...) acquaint themselves with the latest techniques and approaches employed by bench scientists, such as the use of proteomics, genome-wide association studies, and ChIP-on-chip arrays. An overarching theme of this paper is the desirability of bringing closer together the philosophy of science and the practice of scientific research. (shrink)

Can heritability estimates provide causal information? This paper argues for an affirmative answer: since a non-nil heritability estimate satisfies certain characteristic properties of causation (i.e., association, manipulability, and counterfactual dependence), it increases the probability that the relation between genotypic variance and phenotypic variance is (at least partly) causal. Contrary to earlier proposals in the literature, the argument does not assume the correctness of any particular conception of the nature of causation, rather focusing on properties that are characteristic of causal (...) relationships. The argument is defended against Lewontin's (1974) locality objection and Kaplan and Turkheimer's (2021) recent critique of Genome-Wide Association Studies (GWAS). (shrink)

The great majority of phenotypic characteristics are complex traits, complicating the identification of the genes underlying their expression. However, both methodological and theoretical progress in genome‐wide association studies have resulted in a much better understanding of the underlying genetics of many phenotypic traits, including externally visible characteristics (EVCs) such as eye and hair color. Consequently, it has become possible to predict EVCs from human samples lacking phenotypic information. Predicting EVCs from genetic evidence is clearly appealing for forensic (...) applications involving the personal identification of human remains. Now, a recent paper has reported the genetic determination of eye and hair color in samples up to 800 years old. The ability to predict EVCs from ancient human remains opens up promising perspectives for ancient DNA research, as this could allow studies to directly address archaeological and evolutionary questions related to the temporal and geographical origins of the genetic variants underlying phenotypes. (shrink)

It has been known for decades that inference concerning genetic causes of human behavioral phenotypes cannot be legitimately made from correlations among relatives. We claim that these inferential difficulties cannot be overcome by assigning different names to causes inferred from within-family and population-level genome-wide association studies (GWASs). For educational attainment, for example, unraveling gene–environment interactions requires more than new names for causes.

In lieu of an abstract, here is a brief excerpt of the content:The Peculiarly Favored Condition of GeneticsJames J. Lee, PhD (bio) and Damien Morris, MSc (bio)Turkheimer and Greer (2024) (henceforth “T&G”) make some fair points about problems in the scientific profession, including the regrettable tendency to promise practical applications of research that then never materialize. However, T&G’s sustained critique of a body of work associated with one particular researcher to make these general points struck us as uncharitable. More pressingly, (...) we feel that the far-reaching conclusions that T&G attempt to draw from the results they review from the Spit for Science (S4S) cohort are unjustified and risk misleading readers that psychiatric and behavioral genetics is in a parlous state.T&G state that S4S “produced a clear answer to the question it was designed to address,” namely, that its results “unambiguously contradict the hypothesis that alcohol-related behaviors have a meaningful genetic basis.” But S4S cannot possibly have provided affirmative evidence for the null hypothesis, because as a single cohort it lacked the statistical power to do so. Elsewhere T&G acknowledge that the sample size of S4S does not suffice for many purposes; they cannot have it both ways. When GCTA has been applied to samples of greater size, it has unambiguously supported the hypothesis that alcohol-related behaviors have a meaningful genetic basis. The UK Biobank yielded estimates exceeding 0.10 for the contribution of single nucleotide polymorphisms (SNPs) with minor allele frequency of greater than 0.05 to the heritability of drinks per week, estimates more than ten times their standard errors (Liu et al., 2019).This heritability contributed by common variants is sometimes called “SNP heritability,” and T&G disparage it for the alleged “disadvantage of being substantially smaller” than “twin and family heritabilities.” Nowhere do T&G consider what the precise numbers actually mean—an approach that can be hazardous to your scientific health, as the late John Loehlin might have said. Let us, then, consider these numbers. Under a model of pure neutrality, SNP and pedigree narrow-sense heritabilities should be fairly close, essentially as a result of factors p(1 − p) canceling in the multiplication of the numbers of SNPs to be found at a given allele frequency by the average heritability contributed per SNP (Hill, 2010). If SNP and pedigree heritabilities are not close, then natural selection must have been acting on [End Page 441] the trait, preventing new mutations of large effect from becoming common and thereby concentrating heritability at allele frequencies lower than those typically studied in genome-wide association studies (GWAS). This deduction has been abundantly confirmed: the tendency of GWAS SNPs to reside in evolutionarily conserved regions (Finucane et al., 2015; Kim et al., 2019), the younger age of GWAS SNPs when compared to control SNPs of comparable frequencies (Gazal et al., 2017), the discovery of several rare variants with larger effects than those observed in typical GWAS (Barton et al., 2021; Chen et al., 2023; Marouli et al., 2017), the directly measured deleterious fitness effects of mutations in evolutionarily constrained genes (Gardner et al., 2022), and the substantial additional genetic variance accumulated when rare variants are included in GCTA-type studies, sometimes enough to close the gap between SNP and pedigree heritabilities (Evans et al., 2018; Jang et al., 2022; Pathan et al., 2024; Wainschtein et al., 2022).The genetic architecture of a typical quantitative trait consists of many sites across the genome that can mutate to affect it, numbering potentially in the millions (Agarwala et al., 2013; Zeng et al., 2021), of which those that are common SNPs have very small effects as a result of selection. This is the message, but T&G seem to find fault with the messenger, painting “tiny” effect sizes as an embarrassment to the field of behavioral genetics as a whole. We prefer to view the finding of high polygenicity as a revelation about nature, rather than as a debating point. What is this finding telling us? If one takes the action of stabilizing selection as the initial assumption (Uyeda et al., 2011), then the extreme polygenicity revealed by GWAS becomes part of the answer to the question regarding how traits can... (shrink)

We are less optimistic than Madole & Harden that family-based genome-wide association studies (GWASs) will lead to significant second-generation causal knowledge. Despite bearing some similarities, family-based GWASs and randomised controlled trials (RCTs) are not identical. Most RCTs assess a relatively homogenous causal stimulus as a treatment, whereas GWASs assess highly heterogeneous causal stimuli. Thus, GWAS results will not translate so easily into second-generation causal knowledge.

This commentary is a call to action for researchers to create and use genome-wide association studies (GWASs) with previously missed age groups (e.g., infancy, elderly), which will improve our ability to ask important developmental questions using genetic data to trace pathways across the lifespan.

We received 23 spirited commentaries on our target article from across the disciplines of philosophy, economics, evolutionary genetics, molecular biology, criminology, epidemiology, and law. We organize our reply around three overarching questions: (1) What is a cause? (2) How are randomized controlled trials (RCTs) and within-family genome-wide association studies (GWASs) alike and unalike? (3) Is behavior genetics a qualitatively different enterprise? Throughout our discussion of these questions, we advocate for the idea that behavior genetics shares many of (...) the same pitfalls and promises as environmentally oriented research, medical genetics, and other arenas of the social and behavioral sciences. (shrink)

In August of 2018, the results of the largest genomic investigation in human history were published. Scanning the DNA of over one million participants, a genome‐wide association study was conducted to identify genetic variants associated with the number of years of education a person has completed. This measure, called “educational attainment,” is often treated as a proxy for intelligence and cognitive ability. The study raises a host of hard philosophical questions about study design and (...) strength of evidence. It also sets the basis for something far more controversial. Using a new genomic method that generates “polygenic scores,” researchers are now able to use the results of the study to predict a person's educational potential from a blood or saliva sample. Going a step further, some researchers have begun to promote “precision education,” which would tailor students’ school plans to their genetic profiles. The idea of precision education provokes concerns about stigma and self‐fulfilling prophecies. (shrink)

The methodological shift from twin studies to genome-wide association studies (GWASs) diminished estimates of true genetic causation underlying statistical heritability of behavioral differences. The sum total of causal genetic influence on behavior is not zero, but, (a) no one cited in the target article ever thought this was the case, and (b) there is still little known about concrete instances of genetic causation.

Evolutionary gradualism, the randomness of mutations, and the hypothesis that natural selection exerts a pervasive and substantial influence on evolutionary outcomes are pair-wise logically independent. Can the claims about selection and mutation be used to formulate an argument for gradualism? In his Genetical Theory of Natural Selection, R.A. Fisher made an important start at this project in his famous “geometric argument” by showing that a random mutation that has a smaller effect on two or more phenotypes will have a higher (...) average fitness than a random mutation that has a larger phenotypic effect. Motoo Kimura’s demonstration that a gene’s probability of fixation depends on both the selection coefficient and the effective population size shows that Fisher’s argument for gradualism was mistaken. Here we analyze Fisher’s argument and explain how Kimura’s theory leads to a conclusion that Fisher did not anticipate. We identify a fallacy that reasoning about fitness differences and their evolutionary consequences should avoid. We then distinguish forward-directed from backward-directed versions of gradualism. The backward-directed thesis about a single mutation may be correct, but the forward-directed thesis is not. After that we consider a sequence of random mutations that all affect the same cluster of phenotypes and Allen Orr’s idea that there is an optimal sequence of mutation sizes, moving from larger to smaller as the population approaches a fixed optimum. This provides a likelihood justification for a forward-directed version of gradualism when there is a fixed optimum, but it also provides an argument against forward-directed gradualism if the optimum shifts substantially as the population evolves. Finally, we consider whether genome-wide association studies (GWASs) can furnish empirical evidence that bears on the truth of gradualism. The version of gradualism that GWASs directly bear on concerns the phenotypic effect size of a gene after it arises by mutation and has reached an appreciable frequency, not the phenotypic size of the mutation event itself. (shrink)

Intertemporal choice involves deciding between smaller, sooner and larger, later rewards. People tend to prefer smaller rewards that are available earlier to larger rewards available later, a phenomenon referred to as temporal or delay discounting. Despite its ubiquity in human and non-human animals, temporal discounting is subject to considerable individual differences. Here, we provide a critical narrative review of this literature and make suggestions for future work. We conclude that temporal discounting is associated with key socio-economic and health-related variables. Regarding (...) personality, large-scale studies have found steeper temporal discounting to be associated with higher levels of self-reported impulsivity and extraversion; however, effect sizes are small. Temporal discounting correlates negatively with future-oriented cognitive styles and inhibitory control, again with small effect sizes. There are consistent associations between steeper temporal discounting and lower intelligence, with effect sizes exceeding those of personality or cognitive variables, although socio-demographic moderator variables may play a role. Neuroimaging evidence of brain structural and functional correlates is not yet consistent, neither with regard to areas nor directions of effects. Finally, following early candidate gene studies, recent Genome Wide Association Study (GWAS) approaches have revealed the molecular genetic architecture of temporal discounting to be more complex than initially thought. Overall, the study of individual differences in temporal discounting is a maturing field that has produced some replicable findings. Effect sizes are small-to-medium, necessitating future hypothesis-driven work that prioritizes large samples with adequate power calculations. More research is also needed regarding the neural origins of individual differences in temporal discounting as well as the mediating neural mechanisms of associations of temporal discounting with personality and cognitive variables. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The Uselessness of Polygenic Scores for Addressing Campus DrinkingBennett Knox (bio), Hannah Allen (bio), and Stephen M. Downes, PhD (bio)Here we articulate a negative answer to Turkheimer and Greer’s question: “Is it possible to envision a genetically informed program that ethically intervenes on campus drinking?” (Turkheimer & Greer, 2024). However, first, we note that the authors cover an immense amount of ground in their paper. They lend insight into (...) how psychiatric genetics, at its very core, is conducted through their detailed examination of a large body of work in one specific area of this large field. A main result of this is to explain the gulf between results and conclusions, work that provides an invaluable service not just to various areas in philosophy and bioethics, but that are deserving of readership by a very wide audience. This gulf is explained via a careful accounting of the statistical measures used to assess the impact of genes on alcohol-related behavior in the college students sampled and comparisons between the strength of these measures and the strength and scope of conclusions drawn by the Spit for Science (S4S) researchers.A brief mention of the statistical measures in question helps set up our main focus. As Turkheimer and Greer note, before advances in sequencing technology, human behavior geneticists generated heritability coefficients for traits of interest. These coefficients were standardly produced from twin study work, which historically was the best way of getting a sense of the relative contribution of genes to a trait of interest as we cannot, or rather should not, conduct breeding experiments on humans. Current descendants of heritability coefficients come from genome-wide association studies (GWAS), which can be conducted on large groups of unrelated people. One key measure of interest arising from GWAS is a polygenic score (PGS), which “can be thought of as an observed manifestation at the individual level of the abstract variance ratio estimated by a heritability” (Turkheimer & Greer, 2024). Turkheimer and Greer focus on R2 values, which roughly “describe the magnitude of the relationship between the polygenic score and the phenotypes [of interest]” [End Page 437] (Turkheimer & Greer, 2024). They point out that the largest R2 reported in an S4S study is 6.5% (0.065). R2 are taken to be small at 0.01, medium at 0.09, and large at 0.25 in many areas of social science research but there are fields, for example, drug assay work, where only much higher R2 values are considered indication of a large effect. By this assessment, most of the R2 values reported by the S4S researchers, or calculated by Turkheimer and Greer when not reported, are very, very small, sitting well below the level of small effect of 0.01.Given these very low R2 measures, we agree with Turkheimer and Greer that S4S researchers did not uncover genetic information that could be informative, let alone actionable, for administrators concerned with campus drinking. However, it is worth asking what it would have looked like if S4S had produced such information. Suppose that S4S had been wildly successful, producing the Gattaca-like genetic information of “polygenic scores making reliable predictions that individuals had a 35% chance of developing a psychiatric disorder [here, alcoholism]” (Turkheimer & Greer, 2024). If a student was given their PGS, how are they to interpret it and act on it? How would this information be put to use by an administrator to address the problem of campus drinking?For the information to be leveraged at all, it would require consent from a significant number of students to have their PGS calculated and made available to themselves or administrators. Were scores to be calculated without active consent from the student (perhaps by using the sample provided to S4S), this would be a serious ethical violation. But even if a sufficient number of students did consent to having their PGS for alcoholism calculated, it is still not clear how this information could be used in an ethical manner to address the problem of campus drinking.If this student was already aware of a family history of alcoholism, then the PGS might do little more than quantify... (shrink)

Human genetic and genomic research can yield information that may be of clinical relevance to the individuals who participate as subjects of the research. However, no consensus exists as yet on the responsibilities of researchers to disclose individual research results to participants in human subjects research. “Genetic and genomic research” on humans varies widely, including association studies, examination of allele frequencies, and studies of natural selection, human migration, and genetic variation. For the purposes of this article, it is defined (...) broadly to include analysis of DNA collected from humans that has implications for human health. This paper addresses both research results of individual research participants that may be an intended product of the research, as well as unanticipated, “incidental” findings. (shrink)