Validation and genetic heritability estimation of known type 2 diabetes related variants in the Korean population

Genome-wide association studies (GWASs) facilitated the discovery of countless disease-associated variants. However, GWASs have mostly been conducted in European ancestry samples. Recent studies have reported that these European-based association results may reduce disease prediction accuracy when applied in non-Europeans. Therefore, previously reported variants should be validated in non-European populations to establish reliable scientific evidence for precision medicine. In this study, we validated known associations with type 2 diabetes (T2D) and related metabolic traits in 125,850 samples from a Korean population genotyped by the Korea Biobank Array (KBA). At the end of December 2020, there were 8,823 variants associated with glycemic traits, lipids, liver enzymes, and T2D in the GWAS catalog. Considering the availability of imputed datasets in the KBA genome data, publicly available East-Asian T2D summary statistics, and the linkage disequilibrium among the variants (r2 < 0.2), 2,900 independent variants were selected for further analysis. Among these, 1,837 variants (63.3%) were statistically significant (p < 0.05). Most of the non-replicated variants (n = 1,063) showed insufficient statistical power and decreased minor allele frequencies compared with the replicated variants. Moreover, known variants showed <10% genetic heritability. These results could provide valuable scientific evidence for future study designs, the current power of GWASs, and future applications in precision medicine in the Korean population.

Culture is Reducing Genetic Heritability and Superseding Genetic Adaptation

Uchiyama, Spicer, and Muthukrishna reveal how group-structured cultural variation influences measurements of trait heritability. We argue that understanding culture’s influence on phenotypic heritability can clarify the impact of culture on genetic inheritance, which has implications for long-term gene-culture coevolution. Their analysis may provide guidance for testing our hypothesis that cultural adaptation is superseding genetic adaptation in the long term.

Genomic Risk Factors for Cervical Cancer

Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.

PSXV-9 Transgenerational epigenetic variance for production and reproduction traits in maternal-line pigs

Modeling epigenetic factors impacting phenotypic expression of economically important traits has become a hot-topic in the field of animal breeding due to the variability in genetic expression caused by environmental stressors (e.g., heat stress). This variability may be due, in part, to in-utero epigenomic remodeling, which has been reported to be passed from parent to offspring. We aimed to estimate transgenerational epigenetic variance for various production and reproduction traits measured in a maternal-line pig population, using a Bayesian approach. The phenotypes for production [n = 10,862; i.e., weaning weight (WW), birth weight (BW) and ultrasound-backfat thickness (BF)] and reproduction [n = 5,235, i.e., number of piglets born alive (NBA) and total number of piglets born (TB)] traits from a purebred Landrace population were provided by Smithfield Premium Genetics (NC, USA). The pedigree information traced back to 10 generations. Single-trait genetic analyses were performed using mixed models that included additive genetic, common environmental, and epigenetic random effects. The Gibbs sampler algorithm based on Markov chain Monte Carlo was used to estimate the variance components. The epigenetic relationship matrix was constructed using a recursive parameter (λ) related to the transmissibility coefficient of epigenetic markers. A grid search approach was used to define the optimal λ value (λ values ranged from 0.1 to 0.5, with an interval of 0.1). The optimal λ value was determined based on the deviance information criterion, and it was used to estimate the additive and epigenetic variances. For instance, based on preliminary results, the optimal λ value estimated for TB was 0.3 with an additive genetic variance of 0.94 (0.19 PSD) and epigenetic variance of 0.67 (0.18 PSD). The additive genetic heritability was 0.076 (0.015 PSD) and the estimated epigenetic heritability was 0.053 (0.015 PSD). This preliminary result suggests that epigenetics contribute to the non-Mendelian variability in pigs.

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

The genetic etiology of longitudinal measures of predicted brain ageing in a population-based sample of mid to late-age males

Despite their increasing application, the genetic and environmental etiology of global predicted brain ageing (PBA) indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences.

Association of the PINX1 Variant rs6984094, Which Lengthens Telomeres, with Systemic Lupus Erythematosus Susceptibility in Chinese Populations

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified ( P discovery = 4.13 × 10 − 2 , OR = 0.58 , 95% CI 0.35-0.98) and successfully replicated ( P replication = 5.73 × 10 − 3 , OR = 0.45 , 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

Brain charts for the human lifespan

Over the past 25 years, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, there are no reference standards against which to anchor measures of individual differences in brain morphology, in contrast to growth charts for traits such as height and weight. Here, we built an interactive online resource (www.brainchart.io) to quantify individual differences in brain structure from any current or future magnetic resonance imaging (MRI) study, against models of expected age-related trends. With the goal of basing these on the largest and most inclusive dataset, we aggregated MRI data spanning 115 days post-conception through 100 postnatal years, totaling 122,123 scans from 100,071 individuals in over 100 studies across 6 continents. When quantified as centile scores relative to the reference models, individual differences show high validity with non-MRI brain growth estimates and high stability across longitudinal assessment. Centile scores helped identify previously unreported brain developmental milestones and demonstrated increased genetic heritability compared to non-centiled MRI phenotypes. Crucially for the study of brain disorders, centile scores provide a standardised and interpretable measure of deviation that reveals new patterns of neuroanatomical differences across neurological and psychiatric disorders emerging during development and ageing. In sum, brain charts for the human lifespan are an essential first step towards robust, standardised quantification of individual variation and for characterizing deviation from age-related trends. Our global collaborative study provides such an anchorpoint for basic neuroimaging research and will facilitate implementation of research-based standards in clinical studies.

Cultural Evolution of Genetic Heritability

Behavioral genetics and cultural evolution have both revolutionized our understanding of human behavior—largely independent of each other. Here we reconcile these two fields under a dual inheritance framework, offering a more nuanced understanding of the interaction between genes and culture. Going beyond typical analyses of gene–environment interactions, we describe the cultural dynamics that shape these interactions by shaping the environment and population structure. A cultural evolutionary approach can explain, for example, how factors such as rates of innovation and diffusion, density of cultural sub-groups, and tolerance for behavioral diversity impact heritability estimates, thus yielding predictions for different social contexts. Moreover, when cumulative culture functionally overlaps with genes, genetic effects become masked, unmasked, or even reversed, and the causal effects of an identified gene become confounded with features of the cultural environment. The manner of confounding is specific to a particular society at a particular time, but a WEIRD (Western, educated, industrialized, rich, democratic) sampling problem obscures this boundedness. Cultural evolutionary dynamics are typically missing from models of gene-to-phenotype causality, hindering generalizability of genetic effects across societies and across time. We lay out a reconciled framework and use it to predict the ways in which heritability should differ between societies, between socioeconomic levels and other groupings within some societies but not others, and over the life course. An integrated cultural evolutionary behavioral genetic approach cuts through the nature–nurture debate and helps resolve controversies in topics such as IQ.

How Family Histories Can Inform Research About Germ Cell Exposures: The Example of Autism

Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents’ germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASD). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD’s strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of non-genetic heritability in a subset of idiopathic heritable pathologies.