Despite extensive research on global heritability estimation for complex traits, few methods accurately dissect local heritability. A precise local heritability estimate is crucial for ...high-resolution mapping in genetics. Here, we report the effective heritability estimator (EHE) that can use p values from genome-wide association studies (GWASs) for local heritability estimation by directly converting marginal heritability estimates of SNPs to a non-redundant heritability estimate of a gene or a small genomic region. EHE provides higher accuracy and precision for local heritability estimation among seven compared methods. Importantly, EHE can be applied to estimate the conditional heritability of nearby genes, where redundant heritability among the genes can also be removed further. The conditional estimation can be guided by tissue-specific expression profiles (or other functional scores) to prioritize and quantify more functionally important genes of complex phenotypes. Applying EHE to 42 complex phenotypes from the UK Biobank, we revealed the existence of two types of distinct genetic architectures for various complex phenotypes and found that highly pleiotropic genes are not enriched for more heritability compared to other candidate susceptibility genes. EHE provides an accurate and robust way to dissect the genetic architecture of complex phenotypes.
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Miao et al. present EHE, a flexible method for estimating heritability at small genomic regions using p values of SNPs. EHE demonstrates higher accuracy and precision than alternative methods. Additionally, EHE allows for isolating non-redundant conditional heritability of nearby genes, providing valuable insights into the genetic architecture of complex phenotypes.
The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes ...involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.
Resting‐state functional connectivity profiles have been increasingly shown to be important endophenotypes that are tightly linked to human cognitive functions and psychiatric diseases, yet the ...genetic architecture of this multidimensional trait is barely understood. Using a unique sample of 1,704 unrelated, young and healthy Chinese Han individuals, we revealed a significant heritability of functional connectivity patterns in the whole brain and several subnetworks. We further proposed a partitioned heritability analysis for multidimensional functional connectivity patterns, which revealed the common and unique enrichment patterns of the genetic contributions to brain connectivity patterns for several gene sets linked to brain functions, including the genes expressed preferentially in the central nervous system and those associated with intelligence, educational attainment, attention‐deficit/hyperactivity disorder, and schizophrenia. These results for the first time reveal the genetic architecture of multidimensional brain connectivity patterns across different networks and advance our understanding of the complex relationship between gene sets, neural networks, and behaviors.
Using a unique sample of 1,704 unrelated, young and healthy Chinese Han individuals, we revealed a significant heritability of functional connectivity patterns in the whole brain and several subnetworks. We further proposed a partitioned heritability analysis for multidimensional functional connectivity patterns, which revealed the common and unique enrichment patterns of the genetic contributions to brain connectivity patterns for several gene sets linked to brain functions.
Genetics of myopia: Gene finding and beyond Haarman, A. E. G.; Tedja, M. S.; Verhoeven, V. J. M. ...
Acta ophthalmologica (Oxford, England),
December 2022, 2022-12-00, 20221201, Letnik:
100, Številka:
S275
Journal Article
Recenzirano
Odprti dostop
The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. To date, over 500 genetic loci have been identified for refractive error and ...myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. However, also patients with low scores can develop myopia and vice versa. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances including large‐scale, in‐depth genetic studies using complementary big data analytics, consideration of gene–environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence are needed. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.
The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes.
The large-scale recording of traits such as feed ...efficiency (FE) and methane emissions (ME) for use in genetic improvement programs is complex, costly, and time-consuming. Therefore, heritable traits that can be continuously recorded in dairy herds and are correlated with FE and ME traits could provide useful information for genetic evaluation. Rumination time has been suggested to be associated with FE, methane production (MeP; ME in g/d), and production traits at the phenotypic level. Therefore, the objective of this study was to investigate the genetic relationships among rumination time (RT), FE, methane and production traits using 7,358 records from 656 first-lactation Holstein cows. The estimated heritabilities were moderate for RT (0.45 ± 0.14), MeP (0.36 ± 0.12), milk yield (0.40 ± 0.08), fat yield (0.29 ± 0.06), protein yield (0.32 ± 0.07), and energy-corrected milk (0.28 ± 0.07), but were low and nonsignificant for FE (0.15 ± 0.07), which was defined as the residual of the multiple linear regression of DMI on energy-corrected milk and metabolic body weight. A favorable negative genetic correlation was estimated between RT and MeP (−0.53 ± 0.24), whereas a positive favorable correlation was estimated between RT and energy-corrected milk (0.49 ± 0.11). The estimated genetic correlation of RT with FE (−0.01 ± 0.17) was not significantly different from zero but showed a trend of a low correlation with dry matter intake (0.21 ± 0.13). These results indicate that RT is genetically associated with MeP and milk production traits, but high standard errors indicate that further analyses should be conducted to verify these findings when more data for RT, MeP, and FE become available.
•A meta-analysis was conducted for genomic and pedigree-based heritabilities in dairy cows.•The pedigree-based heritability was higher than genomic heritability for all traits.•The gap between ...genomic and pedigree-based heritabilities was high for milk yield.•Moderate heterogeneity was observed for the genomic heritability of milk yield.
This study aimed to conduct a meta-analysis based on a random-effects model to combine different published pedigree-based and genomic heritability estimates for production traits in dairy cows. Also, the missing heritability estimates for the studied traits were determined. In total, 148 heritability estimates from 62 journal articles were used to conduct this meta-analysis. Heterogeneity among studies was evaluated using the I2 index and Chi-square (Q) test. The estimated pedigree-based and genomic heritabilities were 0.253 and 0.144 for milk yield (MY), 0.290 and 0.191 for milk fat percentage (FP), and 0.378 and 0.363 for milk protein percentage (PP), respectively. The gap between genomic and pedigree-based heritability estimates was high for MY (43%) and medium for FP (34%). Also, the difference between genomic and pedigree-based heritabilities was low for PP (11%). Meta-analysis of pedigree-based heritabilities for all traits indicated significant and high heterogeneity. Also, significant and moderate heterogeneity was observed for the genomic heritability of MY. Publication bias was evaluated for genomic heritability of FP and PP that did not indicate significant heterogeneity. Egger's test did not show any significant publication bias for the meta-analysis of genomic heritabilities for FP and PP. This study revealed that estimation of genomic heritabilities by appropriate genotyping and statistical methods could improve the accuracy of genetic parameter estimates for production traits in dairy cows. These estimates would be helpful for future breeding programs and the study of the genetic architecture of production traits in dairy cows.
Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analyse high coverage whole-genome sequencing data, to ...evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants is skewed towards the rare spectrum, and damaging variants are more often rare. We estimate that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identify Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N = 213), and we identify 34 associated loci in Trans. Several associations are driven by rare variants, which have larger effects, on average. We therefore conclude that rare variants could be of importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases.
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