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Genome-wide burden of deleterious coding variants increased in schizophrenia.

Loohuis LM, Vorstman JA, Ori AP, Staats KA, Wang T, Richards AL, Leonenko G, Walters JT, DeYoung J, GROUP ConsortiumCantor RM, Ophoff RA - Nat Commun (2015)

Bottom Line: Schizophrenia is a common complex disorder with polygenic inheritance.At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥ 0.01% in the population.In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, California 90095, USA.

ABSTRACT
Schizophrenia is a common complex disorder with polygenic inheritance. Here we show that by using an approach that compares the individual loads of rare variants in 1,042 schizophrenia cases and 961 controls, schizophrenia cases carry an increased burden of deleterious mutations. At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥ 0.01% in the population. In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study. In addition, the genes implicated by the increased burden of rare coding variants highlight the involvement of neurodevelopment in the aetiology of schizophrenia.

No MeSH data available.


Related in: MedlinePlus

Set-unique SNVs.Diagram depicting the set-unique variants (not to scale, cases n=1,002, controls n=931). The set NS represents all variants that are scored by ISUB, and the set DEL includes only those variants that are predicted to be deleterious. In particular, the set DEL includes stop-altering and splice site variants.
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f1: Set-unique SNVs.Diagram depicting the set-unique variants (not to scale, cases n=1,002, controls n=931). The set NS represents all variants that are scored by ISUB, and the set DEL includes only those variants that are predicted to be deleterious. In particular, the set DEL includes stop-altering and splice site variants.

Mentions: We collected coding sequence variation in 1,042 schizophrenia patients and 961 controls using the Illumina HumanExome BeadChip array. From a total of 100,857 variants observed in our sample, 75,837 are protein-coding SNVs that were scored by ISUB. From these, 16,262 occurred only in cases, of which 6,424 are predicted to be deleterious. For controls, 12,964 were set-unique non-synonymous, with a total of 5,130 predicted to be deleterious (see Fig. 1). The number of observations ranges from 1 to 12 per SNV with a mean of 1.43 (median=1) in cases and a mean of 1.39 (median=1) in controls. The mean MAF of the set-unique variants included in our study is 0.05% in the population based on individuals of European Ancestry included in ESP6500.


Genome-wide burden of deleterious coding variants increased in schizophrenia.

Loohuis LM, Vorstman JA, Ori AP, Staats KA, Wang T, Richards AL, Leonenko G, Walters JT, DeYoung J, GROUP ConsortiumCantor RM, Ophoff RA - Nat Commun (2015)

Set-unique SNVs.Diagram depicting the set-unique variants (not to scale, cases n=1,002, controls n=931). The set NS represents all variants that are scored by ISUB, and the set DEL includes only those variants that are predicted to be deleterious. In particular, the set DEL includes stop-altering and splice site variants.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499856&req=5

f1: Set-unique SNVs.Diagram depicting the set-unique variants (not to scale, cases n=1,002, controls n=931). The set NS represents all variants that are scored by ISUB, and the set DEL includes only those variants that are predicted to be deleterious. In particular, the set DEL includes stop-altering and splice site variants.
Mentions: We collected coding sequence variation in 1,042 schizophrenia patients and 961 controls using the Illumina HumanExome BeadChip array. From a total of 100,857 variants observed in our sample, 75,837 are protein-coding SNVs that were scored by ISUB. From these, 16,262 occurred only in cases, of which 6,424 are predicted to be deleterious. For controls, 12,964 were set-unique non-synonymous, with a total of 5,130 predicted to be deleterious (see Fig. 1). The number of observations ranges from 1 to 12 per SNV with a mean of 1.43 (median=1) in cases and a mean of 1.39 (median=1) in controls. The mean MAF of the set-unique variants included in our study is 0.05% in the population based on individuals of European Ancestry included in ESP6500.

Bottom Line: Schizophrenia is a common complex disorder with polygenic inheritance.At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥ 0.01% in the population.In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, California 90095, USA.

ABSTRACT
Schizophrenia is a common complex disorder with polygenic inheritance. Here we show that by using an approach that compares the individual loads of rare variants in 1,042 schizophrenia cases and 961 controls, schizophrenia cases carry an increased burden of deleterious mutations. At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥ 0.01% in the population. In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study. In addition, the genes implicated by the increased burden of rare coding variants highlight the involvement of neurodevelopment in the aetiology of schizophrenia.

No MeSH data available.


Related in: MedlinePlus