From Genotype to Phenotype: Polygenic Prediction of Complex Human Traits

Raben, Timothy G.; Lello, Louis; Widén, Erik; Hsu, Stephen

doi:10.1007/978-1-0716-2205-6_15

Cited by 3 publications

(1 citation statement)

References 153 publications

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“…The PRS is a quantitative measure of the individual genetic burden for a trait based on data from Genome-Wide Association Studies (GWAS). Although PRS methods do not yet provide clinically feasible information in psychiatric disorders 54 , schizophrenia PRSs are highly informative for assessing the individual risk for the disorder at the research level and are highly consistent across studies and samples 55 . PRSs can be calculated on a genome-wide basis, but also within subsets of SNPs defined according to their affiliation to specific biological pathways of interest 56 .…”

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confidence: 99%

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Guardiola-Ripoll,

Almodóvar-Payá,

Arias-Magnasco

et al. 2023

Commun Biol

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Schizophrenia may represent a trade-off in the evolution of human-specific ontogenetic mechanisms that guide neurodevelopment. Human Accelerated Regions (HARs) are evolutionary markers functioning as neurodevelopmental transcription enhancers that have been associated with brain configuration, neural information processing, and schizophrenia risk. Here, we have investigated the influence of HARs’ polygenic load on neuroanatomical measures through a case-control approach (128 patients with schizophrenia and 115 controls). To this end, we have calculated the global schizophrenia Polygenic Risk Score (Global PRSSZ) and that specific to HARs (HARs PRSSZ). We have also estimated the polygenic burden restricted to the HARs linked to transcriptional regulatory elements active in the foetal brain (FB-HARs PRSSZ) and the adult brain (AB-HARs PRSSZ). We have explored the main effects of the PRSs and the PRSs x diagnosis interactions on brain regional cortical thickness (CT) and surface area (SA). The results indicate that a higher FB-HARs PRSSZ is associated with patients’ lower SA in the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule. While noHARs-derived PRSs show an effect on the risk, our neuroanatomical findings suggest that the human-specific transcriptional regulation during the prenatal period underlies SA variability, highlighting the role of these evolutionary markers in the schizophrenia genomic architecture.

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confidence: 99%

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Guardiola-Ripoll,

Almodóvar-Payá,

Arias-Magnasco

et al. 2023

Commun Biol

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Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations

Capalbo,

de Wert,

Mertes

et al. 2024

Human Reproduction Update

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BACKGROUND The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing. OBJECTIVE AND RATIONALE This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom. SEARCH METHODS We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms ‘polygenic embryo screening’, ‘polygenic preimplantation’, and ‘PGT-P’. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant. OUTCOMES The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for ‘designer babies’, overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling. WIDER IMPLICATIONS The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling.

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Polygenic predictions of occupational status GWAS elucidate genetic and environmental interplay for intergenerational status transmission, careers, and health

Akimova

Wolfram

Ding

et al. 2023

Preprint

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Socioeconomic status (SES) stratifies society and impacts our health and life course. We conducted the first sociologically informed GWAS on occupational status and prestige examining the International Socioeconomic Index (ISEI), the Standard International Occupational Prestige Scale (SIOPS) and the Cambridge Social Interaction and Stratification Scale (CAMSIS), on 273,157 individuals from the UK Biobank. We identified 106 genetic variants of which 8 are novel to the study of the genetics of SES. Out-of-sample prediction explained up to 9% of individual differences in occupational status and remains predictive within families. Cognitive and non-cognitive traits - including scholastic and occupational motivation and aspiration - largely mediated genetic effects. Genetic inheritance explained up to 40% of the intergenerational transmission of occupational status. Furthermore, the associations between genetics, occupation, and health are interrelated rather than independent. Across the professional career, genetic stratification compresses during mid-careers as the status scissor reopens towards their end.

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From Genotype to Phenotype: Polygenic Prediction of Complex Human Traits

Cited by 3 publications

References 153 publications

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia

Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations

Polygenic predictions of occupational status GWAS elucidate genetic and environmental interplay for intergenerational status transmission, careers, and health

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