Dataset Information

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.

ABSTRACT: OBJECTIVES:Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred. METHODS:We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide. RESULTS:We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500?kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3-6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission. CONCLUSION:Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry.

SUBMITTER: Melhem NM

PROVIDER: S-EPMC5572483 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.

Melhem Nadine M NM Hamdan Sami S Klei Lambertus L Wood Shawn S Zelazny Jamie J Frisch Amos A Weizman Abraham A Carmel Miri M Michaelovsky Elena E Farbstein Ilana I Wasserman Danuta D El-Heib Muhammad M Ferrell Robert R Apter Alan A Devlin Bernie B Brent David D

Psychiatric genetics 20171001 5

<h4>Objectives</h4>Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred.<h4>Methods</h4>We carried out genetic analyses of 439 ind ...[more]

PMID: 28570395

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Project description:Pedigree information was traditionally used to assess inbreeding. The availability of high-density marker panels provides an alternative to assess inbreeding, particularly in the presence of incomplete and error-prone pedigrees. Assessment of autozygosity across chromosomal segments using runs of homozygosity (ROH) has emerged as a valuable tool to estimate inbreeding due to its general flexibility and ability to quantify the chromosomal contribution to genome-wide inbreeding. Unfortunately, the identification of ROH segments is sensitive to the parameters used during the search process. These parameters are heuristically set, leading to significant variation in the results. The minimum length required to identify an ROH segment has major effects on the estimation of inbreeding and inbreeding depression, yet it is arbitrarily set. To overcome this limitation, a search algorithm to approximate mutation enrichment was developed to determine the minimum length of ROH segments. It consists of finding genome segments with significant effect differences in trait means between animals with high and low burdens of autozygous intervals with a specific length. The minimum length could be determined heuristically as the smallest interval at which a significant signal is detected. The proposed method was tested in an inbred Hereford cattle population genotyped for 30,220 SNPs. Phenotypes recorded for six traits were used for the approximation of mutation loads. The estimated minimum length was around 1 Mb for yearling weight (YW) and average daily gain (ADG) and 4 Mb for birth weight and weaning weight. These trait-specific thresholds estimated using the proposed method could be attributed to a trait-dependent effect of homozygosity. The detection of significant inbreeding effects was well aligned with the estimated thresholds, especially for YW and ADG. Although highly deleterious alleles are expected to be more frequent in recent inbreeding (long ROH), short ROH segments (<5 Mb) could contain a large number of less deleterious mutations with substantial joint effects on some traits (YW and ADG). Our results highlight the importance of accurate estimation of the ROH-based inbreeding and the necessity to consider a trait-specific minimum length threshold for the identification of ROH segments in inbreeding depression analyses. These thresholds could be determined using the proposed method provided the availability of phenotypic information.

Project description:Runs of homozygosity (ROH) islands are stretches of homozygous sequence in the genome of a large proportion of individuals in a population. Algorithms for the detection of ROH depend on the similarity of haplotypes. Coverage gaps and copy number variants (CNV) may result in incorrect identification of such similarity, leading to the detection of ROH islands where none exists. Misidentified hemizygous regions will also appear as homozygous based on sequence variation alone. Our aim was to identify ROH islands influenced by marker coverage gaps or CNV, using Illumina BovineHD BeadChip (777 K) single nucleotide polymorphism (SNP) data for Austrian Brown Swiss, Tyrol Grey and Pinzgauer cattle.ROH were detected using clustering, and ROH islands were determined from population inbreeding levels for each marker. CNV were detected using a multivariate copy number analysis method and a hidden Markov model. SNP coverage gaps were defined as genomic regions with intermarker distances on average longer than 9.24 kb. ROH islands that overlapped CNV regions (CNVR) or SNP coverage gaps were considered as potential artefacts. Permutation tests were used to determine if overlaps between CNVR with copy losses and ROH islands were due to chance. Diversity of the haplotypes in the ROH islands was assessed by haplotype analyses.In Brown Swiss, Tyrol Grey and Pinzgauer, we identified 13, 22, and 24 ROH islands covering 26.6, 389.0 and 35.8 Mb, respectively, and we detected 30, 50 and 71 CNVR derived from CNV by using both algorithms, respectively. Overlaps between ROH islands, CNVR or coverage gaps occurred for 7, 14 and 16 ROH islands, respectively. About 37, 44 and 52% of the ROH islands coverage in Brown Swiss, Tyrol Grey and Pinzgauer, respectively, were affected by copy loss. Intersections between ROH islands and CNVR were small, but significantly larger compared to ROH islands at random locations across the genome, implying an association between ROH islands and CNVR. Haplotype diversity for reliable ROH islands was lower than for ROH islands that intersected with copy loss CNVR.Our findings show that a significant proportion of the ROH islands in the bovine genome are artefacts due to CNV or SNP coverage gaps.

Project description:BackgroundExome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.MethodsIn a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.ResultsThe QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.ConclusionsOur clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

Dataset Information

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.

Publications

Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.

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