Dataset Information

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

ABSTRACT: We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.

SUBMITTER: Mahmood T

PROVIDER: S-EPMC8084434 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

Mahmood Tariq T El-Asrag Mohammed E ME Poulter James A JA Cardno Alastair G AG Tomlinson Anneka A Ahmed Sophia S Al-Amri Ahmed A Nazari Jamshid J Neill Joanna J Chamali Rifka S RS Kiwan Nancy N Ghuloum Suhaila S Alhaj Hamid A HA Randerson Moor Juliette J Khan Shabana S Al-Amin Hassen H Johnson Colin A CA Woodruff Peter P Wilkinson Iain D ID Ali Manir M Clapcote Steven J SJ Inglehearn Chris F CF

Schizophrenia bulletin 20210401 3

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for ...[more]

PMID: 33159203

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Project description:Maize lethal necrosis (MLN) is a viral disease with a devastating effect on maize production. Developing and deploying improved varieties with resistance to the disease is important to effectively control MLN; however, little is known about the causal genes and molecular mechanism(s) underlying MLN resistance. Screening thousands of maize inbred lines revealed KS23-5 and KS23-6 as two of the most promising donors of MLN resistance alleles. KS23-5 and KS23-6 lines were earlier developed at the University of Hawaii, United States, on the basis of a source population constituted using germplasm from Kasetsart University, Thailand. Both linkage mapping and association mapping approaches were used to discover and validate genomic regions associated with MLN resistance. Selective genotyping of resistant and susceptible individuals within large F2 populations coupled with genome-wide association study identified a major-effect QTL (qMLN06_157) on chromosome 6 for MLN disease severity score and area under the disease progress curve values in all three F2 populations involving one of the KS23 lines as a parent. The major-effect QTL (qMLN06_157) is recessively inherited and explained 55%-70% of the phenotypic variation with an approximately 6 Mb confidence interval. Linkage mapping in three F3 populations and three F2 populations involving KS23-5 or KS23-6 as one of the parents confirmed the presence of this major-effect QTL on chromosome 6, demonstrating the efficacy of the KS23 allele at qMLN06.157 in varying populations. This QTL could not be identified in population that was not derived using KS23 lines. Validation of this QTL in six F2 populations with 20 SNPs closely linked with qMLN06.157 was further confirmed its consistent expression across populations and its recessive nature of inheritance. On the basis of the consistent and effective resistance afforded by the KS23 allele at qMLN06.157, the QTL can be used in both marker-assisted forward breeding and marker-assisted backcrossing schemes to improve MLN resistance of breeding populations and key lines for eastern Africa.

Project description:Aims/hypothesisIn a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects.MethodsWe investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model.ResultsUsing a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10-8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10-7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10-8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations.Conclusions/interpretationWe demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations.Data availabilityThe Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/ ) under the accession EGAS00001002641.

Dataset Information

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

Publications

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

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