Highly Recurrent Copy Number Variations in GABRB2 Associated With Schizophrenia and Premenstrual Dysphoric Disorder

2021

Hum Genomics

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Background Genetic variants, underlining phenotypic diversity, are known to distribute unevenly in the human genome. A comprehensive understanding of the distributions of different genetic variants is important for insights into genetic functions and disorders. Methods Herein, a sliding-window scan of regional densities of eight kinds of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs) in the human genome has been performed. Results The study has identified 44,379 hotspots with high genetic-variant densities, and 1135 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.2% of the genome respectively. The hotspots and clusters are found to co-localize with different functional genomic features, as exemplified by the associations of hotspots of middle-size CNVs with histone-modification sites, work with balancing and positive selections to meet the need for diversity in immune proteins, and facilitate the development of sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths co-localize with retrotransposons of different ages on a “long-with-young” and “short-with-all” basis. Hotspots and clusters are highly associated with tumor suppressor genes and oncogenes (p < 10−10), and enriched with somatic tumor CNVs and the trait- and disease-associated SNPs identified by genome-wise association studies, exceeding tenfold enrichment in clusters comprising SNPs and extra-long CNVs. Conclusions In conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes. Their strong associations with complex traits and diseases also open up a potential “Common Disease-Hotspot Variant” approach to the missing heritability problem.

Section: Discussionmentioning

confidence: 99%

Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability

2021

Hum Genomics

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“…The overlaps of genes of nicotine addiction, glutamatergic synapses, olfactory transduction, alcoholism, systemic lupus erythematosus, hypogonadism, premature ovarian failure, and breast cancer with PMDD might be suggestive of hitherto hidden aspects of central nervous system or endocrine system involvements with PMDD. The GRIA4 gene, overlapping with the 100-kb CNV features for the C>D and V>D comparisons, groups, has also been found to be associated with schizophrenia (38), in accordance with the shared CNVs between schizophrenia and PMDD (14).…”

Section: Discussionmentioning

confidence: 60%

“…Deletion of gabrb2 genes from knockout mice also brought about schizophrenic symptoms that were alleviated by the antipsychotic Risperidone (13). Recently, analysis of germline copy-number-variations (CNVs) at the nsv1177513 site in Exon 11, and the esv2730987 site in Intron 6, of GABRB2 in PMDD and schizophrenia patients showed that CNV alterations at both esv2730987 and nsv1177513 were significantly associated with schizophrenia in Chinese and Germans as well as PMDD in Chinese (14). Moreover, subjects with different levels of susceptibility to cancer could be distinguished by means of diagnostic CNV marker features selected from the germline genomes with the application of machine learning (15).…”

Section: Introductionmentioning

confidence: 99%

Copy number variation profile-based genomic subtyping of premenstrual dysphoric disorder in Chinese

et al. 2021

Preprint

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Premenstrual dysphoric disorder (PMDD) affects nearly 5% women of reproductive age. The symptomatic heterogeneity, along with largely unknown genetics, of PMDD have greatly hindered its effective treatment. In the present study, 127 Chinese PMDD patients of the 'invasion' and 'depression' subtypes clinically differentiated by us earlier were analyzed together with 108 non-PMDD controls for genome-wide copy number variations (CNVs). Germline genomic DNA samples from white blood cells were subjected to AluScan sequencing-based CNV profiling, which enabled clustering of patient samples readily into the V and D groups, dominated by the "invasion" and "depression" clinical subtypes, respectively; the CNVs obtained with 100-kb windows yielded two clusters that were correlated with these subtypes with a consistency of up to 89.8%. Diagnostic correlation- and frequency-based CNV features of either CNV-gain (CNVG) or CNV-loss (CNVL) that could differentiate between V and D subtypes were selected and analyzed. CNVG features located preferentially in S2-phase replicating regions and enriched with steroid hormone biosynthesis pathway of genes were found protective against PMDD. Moreover, machine learning employing the correlation-based CNV features could predict with >80% accuracy whether a genomic sample was D-type, V-type or control. In terms of their CNV profiles, the D- and V-types differed more from one another than from the controls, thereby providing a genomic basis for the clinical D-V subtyping of PMDD. Genome-wide profiling of CNVs, as a new approach to complex disease genetics, has revealed recurrent CNVs and genomic features beyond individual genes and mutations underlying PMDD clinical diversity.

“…and SNPs, haplotypes and CNVs in the 3,551-bp segment are found to be associated with schizophrenia taking a candidate gene approach [92,93]. However, genome-wide association studies report no significant association between any of the SNPs in this 3,551-bp segment and schizophrenia.…”

Section: Positive Effects Of Hotspots and Clustersmentioning

confidence: 99%

Genetic-variant hotspots and hotspot clusters in the human genome facilitating adaptation while increasing instability

2020

Preprint

Self Cite

Background: Genetic variants, underlining phenotypic diversity, are known to distribute unevenly in the human genome. A comprehensive understanding of the distributions of different genetic variants is important for insights into genetic functions and disorders. Methods: Herein, a sliding-window scan of regional densities of eight kinds of germline genetic variants, including single-nucleotide-polymorphisms (SNPs) and four size-classes of copy-number-variations (CNVs) in the human genome has been performed. Results: The study has identified 44,379 hotspots with high genetic-variant densities, and 1,135 hotspot clusters comprising more than one type of hotspots, accounting for 3.1% and 0.2% of the genome respectively. The hotspots and clusters are found to co-localize with different functional genomic features, as exemplified by the associations of hotspots of middle-size CNVs with histone-modification sites, work with balancing and positive selections to meet the need for diversity in immune proteins, and facilitate the development of sensory-perception and neuroactive ligand-receptor interaction pathways in the function-sparse late-replicating genomic sequences. Genetic variants of different lengths co-localize with retrotransposons of different ages on a 'long-with-young' and 'short-with-all' basis. Hotspots and clusters are highly associated with tumour suppressor genes and oncogenes (p < 10-10), and enriched with somatic tumour CNVs and the trait- and disease-associated SNPs identified by genome-wise association studies, exceeding tenfold enrichment in clusters comprising SNPs and extra-long CNVs. Conclusions: In conclusion, the genetic-variant hotspots and clusters represent two-edged swords that spearhead both positive and negative genomic changes. Their strong associations with complex traits and diseases also open up a potential 'Common Disease-Hotspot Variant' approach to the missing heritability problem.