Family-based genetic risk prediction of multifactorial disease

Genome-wide association studies have detected dozens of variants underlying complex diseases, although it is uncertain how often these discoveries will translate into clinically useful predictors. Here, to improve genetic risk prediction, we consider including phenotypic and genotypic information from related individuals. We develop and evaluate a family-based liability-threshold prediction model and apply it to a simulation of known Crohn's disease risk variants. We show that genotypes of a relative of known phenotype can be informative for an individual's disease risk, over and above the same locus genotyped in the individual. This approach can lead to better-calibrated estimates of disease risk, although the overall benefit for prediction is typically only very modest

Second-generation PLINK: rising to the challenge of larger and richer datasets

PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.Comment: 2 figures, 1 additional fil

Genetic modifiers and subtypes in schizophrenia: Investigations of age at onset, severity, sex and family history

Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified. We performed genome-wide association studies (GWAS) examining genetic influences on age at onset (AAO) and illness severity as well as specific risk by sex or family history status using up to 2762 cases and 3187 controls from the International Schizophrenia Consortium (ISC)

Soybean Management for Seed Composition: The Perspective of U.S. Farmers

The soybean [Glycine max (L.) Merr.] compositional quality is mainly provided by the seed concentration of protein and oil. These traits are critical for sustaining global use, and although there is demand for high protein soybean, no mechanism to differentiate production is in place. At the opposite end of the supply chain, farmers are remunerated on a mass basis without having any incentive regarding seed composition. This study evaluated farmers\u27 perspectives and knowledge on soybean quality and their propensity to adopt quality improvement technologies. Farmers from the main U.S. producing regions (n = 271) were investigated with a self-administrated survey containing 21 questions during 2020 and 2021. Our results show that 84% are unaware of the current protein and oil levels from their own production. A small portion (1.4%) make management decisions (e.g., choice of genotypes or monitor quality) based on the implications on seed quality. However, practices already in place are likely to enhance the quality of seed, namely N nutrition (via rhizobia [12.9%] or fertilizer [5.9%]) and late-season crop protection (17.1%). If farmers are financially rewarded by US$0.50 per bushel, a mindset change may occur. Based on these results, we concluded that shifts in the U.S. production system targeting protein or oil markets are possible, and the constraints are mainly related to on-farm management. However, the challenges for improving the U.S. soybean competitiveness in global or niche markets also rely upon other segments of the production chain, specifically breeders, technology suppliers, and logistical structure

De novo CNVs in bipolar affective disorder and schizophrenia

An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations

Soybean yield, biological N2 fixation and seed composition responses to additional inoculation in the United States

It is unclear if additional inoculation with Bradyrhizobia at varying soybean [Glycine max (L.) Merr.] growth stages can impact biological nitrogen fixation (BNF), increase yield and improve seed composition [protein, oil, and amino acid (AA) concentrations]. The objectives of this study were to evaluate the effect of different soybean inoculation strategies (seed coating and additional soil inoculation at V4 or R1) on: (i) seed yield, (ii) seed composition, and (iii) BNF traits [nodule number and relative abundance of ureides (RAU)]. Soybean field trials were conducted in 11 environments (four states of the US) to evaluate four treatments: (i) control without inoculation, (ii) seed inoculation, (iii) seed inoculation + soil inoculation at V4, and (iv) seed inoculation + soil inoculation at R1. Results demonstrated no effect of seed or additional soil inoculation at V4 or R1 on either soybean seed yield or composition. Also, inoculation strategies produced similar values to the non-inoculated control in terms of nodule number and RAU, a reflection of BNF. Therefore, we conclude that in soils with previous history of soybean and under non-severe stress conditions (e.g. high early-season temperature and/or saturated soils), there is no benefit to implementing additional inoculation on soybean yield and seed composition.Fil: Carciochi, Walter Daniel. Kansas State University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Moro Rosso, Luiz H.. Kansas State University; Estados UnidosFil: Secchi, Mario Alberto. Kansas State University; Estados UnidosFil: Torres, Adalgisa R.. Kansas State University; Estados UnidosFil: Naeve, Seth. University of Minnesota; Estados UnidosFil: Casteel, Shaun N.. Purdue University; Estados UnidosFil: Kovács, Péter. University of South Dakota; Estados UnidosFil: Davidson, Dan. Illinois Soybean Association; Estados UnidosFil: Purcell, Larry C.. University of Arkansas for Medical Sciences; Estados UnidosFil: Archontoulis, Sotirios. University of Iowa; Estados UnidosFil: Ciampitti, Ignacio A.. Kansas State University; Estados Unido

Cis-Acting Regulation of Brain-Specific ANK3 Gene Expression by a Genetic Variant Associated with Bipolar Disorder

Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology