a genome-wide association study of copy number variation in schizophrenia
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A Genome-wide association study of Copy number variation in schizophrenia. Andrés Ingason CNS Division, deCODE Genetics. Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital. Common variant – common disease. - PowerPoint PPT PresentationTRANSCRIPT
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A Genome-wide association study of Copy number variation in
schizophrenia
Andrés Ingason
CNS Division, deCODE Genetics.
Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital.
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Common variant – common disease
• The development of SNP microarrays providing genotypes for hundreds of thousands of markers at an affordable price has paved the way for the identification of at-risk genes for many common diseases
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Nicotine addiction / lung cancer
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Schizophrenia– all quiet on the western front
• Many studies using large samples have been conducted in schizophrenia (and other psyciatric disorders for that matter) since the introduction of genome-wide SNP microarrays, without producing unanimous positive results.
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Why are psychatric diseases different?Why do we not find susceptibility variants?
• Reduced fecundity, associated with disorders such as autism, schizophrenia and mental retardation, places negative selection pressure on haplotypes carrying risk alleles.
• The genetic risk of diseases under such pressure is less likely to be accounted for by common low penetrant variants.
• Instead rare, more penetrant mutations at many sites across the genome may be involved and account for a proportion of the genetic risk.
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Can we find rare high risk variants with current technology?
• In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide arrays.
• This has led to the identification of CNVs associated with mental retardation and autism.
• Walsh et al. report very recently of CNVs being involved in schizophrenia as well
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How can the prevalence of schizophrenia be reconciled with the
existence of rare high risk CNVs under negative selection ?
• Genomic regions flanked by low copy repeats (LCR) prone to non-allelic homologous recombination (NAHR) provide sites for recurrent CNV events
• These CNVs should appear more often as de novo upon inspection when under negative selection pressure.
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Study designIdentification of de novo CNVsDosageMiner, software that identifies CNVs from chip data~2200 trios genotyped on Illumina chips~5700 parent-offspring pairs genotyped on Illumina chips~10100 transmissions to identify de novo deletions~4400 transmissions to identify de novo duplicationsQuality Control
Association Study (SGENE sample)~1,500 Schizophrenia patients genotyped on Illumina chips~30,000 controls genotyped on Illumina microarrays
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DosageMiner
• Signal intensities from SNPs on Illumina chips are normalized to reduce noise
• Sample effect• SNP/genotype effect• GC content effect
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DosageMiner
Black dots: normalized intensity of SNP
Red dots: moving average intensity
Blue line: Deletion, as defined by DosageMiner
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DosageMiner
Black dots: normalized intensity of SNP
Red dots: moving average intensity
Green line: Duplication, as defined by DosageMiner
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Quality ControlSize matters
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Quality ControlSize matters
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Quality ControlSample matters
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De novo CNVs in trios
• For the 2189 trios, we query the offspring for all deletions and duplications (as reported by DosageMiner) in autosomal chromosomes spanning at least 10 consecutive SNP markers.
• We use the overall variance in SNP intensities for each offspring, to estimate the quality of the intensity data
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De novo CNVs in trios
2057 trio-offspring with mean variance <300(arbitrary cutoff value approx. 2SD>mean of all samples)
Chip Trios CNVs 317k 891 17.046DUO 809 15.683370k 357 14.455
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De novo CNVs in trios
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CNVs/PN
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Ns
317k PNs
DUO PNs
370k PNs
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De novo CNVs in triosNoise vs. CNVs pr. PN
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CNVs/PN
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Vs
Chr2
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De novo CNVs in trios
Chip 317k DUO 370k
PN ratio 0.74 0.77 0.64
CNVs 2028 1589 698
CNV ratio 0.12 0.10 0.05
Using only samples with <10 reported CNVs we retain most of the power (73% of samples) while we get rid of most of the noise.
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De novo CNVs in triosPower of detection (n=1500)
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population frequency
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De novo CNVs in trios
Offspring
Father
Mother
Offspring
Father
Mother
De novo deletion or false calling
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CNV length Accuracy N CNVs %
10-14 0.42 326 137 0.55
15-19 0.61 69 42 0.17>19 0.89 80 71 0.28
Data from 317k trios, chr1-4
De novo CNVs in trios
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Chip 317k DUO 370k
CNVs >9 SNP 2028 1589 698
CNVs >19 SNP 439 333 122
>19 SNP / >9 SNP 0.22 0.21 0.18
De novo CNVs in trios
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De novo CNVs in parent-offspring pairs
• We used LOH analysis combined with DosageMiner data to identify de novo deletions in offspring where only one parent is genotyped.
• When 2 or more inheritence errors with genotyped parent were found in a stretch of homozygous markers in offspring, and DosageMiner revealed deletion in offspring and not in genotyped parent we conclude that the deletion is de novo.
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De novo CNVs in parent-offspring pairs
Genotyped parent
Offspring
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De novo CNVs - results
• We found 70 de novo CNVs at 66 loci• 55 deletions and 15 duplications• 4 deletions observed de novo twice• 20 deletions and 6 duplications observed in
the 1600 vs. 30000 sample• 8 deletions and 2 duplications observed in the
schizophrenia sample• 3 deletions showed nominal association to
schizophrenia
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De novo CNVs - resultsChromosome Deletions Duplications CNVs
Chr1 3 1 4 (3)
Chr2 4 2 6
Chr3 4 1 5
Chr4 1 1
Chr5 2 2
Chr6 2 2
Chr7 6 3 9
Chr8 1 1
Chr9 1 1
Chr10 3 3
Chr11 1 1 2
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De novo CNVs - resultsChromosome Deletions Duplications CNVs
Chr12 1 1 2
Chr13
Chr14
Chr15 3 2 5 (4)
Chr16 10 (7) 10 (7)
Chr17 4 1 5
Chr18 1 1
Chr19 2 1 3
Chr20 4 (3) 4 (3)
Chr21 1 1
Chr22 3 3
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Premutations could provide another mechanism for recurrent CNVs in severe psyciatric disorders.
Father
Mother
Offspring
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Complete GW-CNV studies
• Next step is to finish inspecting the 4000 or so candidate CNVs from the 1500 trios to give us a fixed set of confirmed CNVs of >50-100 Kb in >0.001 population frequency.
• This is already well underway, and when finished can be used as a basis for studies in other diseases/traits as well.
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Take home message
• Recurrent CNVs may be involved in schizophrenia as well as autism and mental retardation and other severe psychiatric disorders where reduced fecundity is observed
• Analysing CNVdata from GW SNP chips requires much effort to read through the noise.
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Thanks to....
• all my coworkers at decode
• the collaborators in SGENE
• EC for funding SGENE
• the participants of the study
• the organisers for inviting me
• you for listening