CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics

May combine two claims.

Among bipolar disorder cases with onset before age 18, the de novo CNV rate was 5.6%, comparable to the 4.5% rate observed in schizophrenia using the same methods.

“The rate of de novo CNVs among cases with an age at onset younger than 18 was higher still (5.6%), and comparable to the rate we observed in schizophrenia (4.5%) using the same methods.”

• cites Malhotra et al., 2011 sourceNot checked yet

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In bipolar disorder, de novo CNV frequency was 4.3%, significantly higher than the 0.09% found in healthy controls.

“Frequencies of de novo CNVs were significantly higher (4.3%) in bipolar disorder as compared with healthy individuals(0.09%).”

• cites Malhotra et al., 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

NAHR requires alignment and crossing over between two genomic sites that share sequence homology.

“NAHR involves the alignment and subsequent crossing over between two sites in the genome that share region of sequence homology (Figure 2A).”

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Although SNPs are about 1,000 times more numerous than CNVs, the two classes contribute similarly to genomic variation when measured in nucleotides.

“Although SNPs outnumber CNVs in the genome by three orders of magnitude, their relative contributions to genomic variation (as measured in nucleotides) are similar.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most structural variants can be explained by four main mechanisms: NAHR, NHEJ, FoSTeS, and L1-mediated retrotransposition.

“Four major mechanisms can account for the majority of SVs: non allelic homologous recombination (NAHR), non homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and L1-mediated retrotransposition (Zhang et al., 2009b)(Figure 2).”

• cites Zhang et al., 2009bNot checked yet

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Human genomes carry on average more than 1,000 CNVs, amounting to about 4 million base pairs of difference.

“On average, there are >1000 CNVs in the genome, accounting for ~4 million base pairs of genomic difference (Conrad et al., 2010; Mills et al., 2011).”

• cites Conrad et al., 2010 sourceNot checked yet

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• cites Mills et al., 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NAHR occurs during meiosis and, less often, in mitotically dividing cells.

“NAHR can occur both in meiosis (Turner et al., 2008) and, at lower frequency, in mitotically-dividing cells as well (Lam and Jeffreys, 2006, 2007).”

• cites Turner et al., 2008 sourceNot checked yet

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• cites Lam and Jeffreys, 2006, 2007Not checked yet

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Early insights into rare genetic causes of common disease have come from CNVs and de novo CNVs.

“Perhaps naturally, the early insights into the rare genetic causes of common disease have emerged from these classes of variants.”

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NHEJ arises from faulty repair of DNA double-strand breaks and is more error-prone than NAHR.

“NHEJ occurs as a result of the aberrant repair of DNA double strand breaks and is guided entirely by the information contained within or near the DNA lesion for repair, which makes it error prone as compared to NAHR (Lieber, 2008) (Figure 2B).”

• cites Lieber, 2008 sourceNot checked yet

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Even though the absolute structural mutation rate is low, individual mutations can span tens to thousands of kilobases, so overall genomic change is about 1,000 bp per generation and the functional impact per site is large.

“Although the absolute rate of structural mutation is low, individual mutations may affect tens or thousands of kilobases. Therefore, the overall rate of genomic change (as measured in nucleotides) is high, on the order of 1,000 bp per generation, and the functional impact per site is large.”

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In Sebat et al. 2007, de novo CNV rates were 10% in idiopathic ASD simplex cases, 2% in multiplex families, and 1% in unaffected controls.

“In this study, a high rate of de novo CNVs in idiopathic ASD cases from simplex families (10%) was observed compared to the rate in cases from multiplex families (2%) or unaffected controls (1%).”

• cites Sebat et al., 2007 sourceNot checked yet

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FoSTeS/MMBIR-generated rearrangements vary widely in size and complexity.

“Genomic rearrangements generated by FoSTeS/MMBIR can vary greatly in size and complexity (Hastings et al., 2009b; Zhang et al., 2009c).”

• cites Hastings et al., 2009bNot checked yet

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• cites Zhang et al., 2009cNot checked yet

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Both germline and somatic L1 activity make substantial contributions to structural variation in human genomes.

“Both germline and somatic L1 activity contribute significantly to structural variation in human genomes (Lupski, 2010).”

• cites Lupski, 2010 sourceNot checked yet

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New retrotransposon insertions probably account for most smaller structural mutation events, with Alu insertions at about 0.05 per generation and L1 insertions at about 0.01-0.05 per generation.

“New retrotransposon insertions probably account for the majority of smaller events, with short (300 basepairs) Alu repeat insertions occurring at a rate of 0.05 per generation (Cordaux and Batzer, 2009) and longer (1000–9000 bp) L1 insertions occurring at a rate of 0.01–0.05. per generation (Beck et al., 2011).”

• cites Cordaux and Batzer, 2009Not checked yet

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• cites Beck et al., 2011 sourceNot checked yet

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NHEJ may be promoted by certain genomic architectures but does not require extensive sequence homology.

“This suggests that NHEJ may be stimulated by certain genomic architectures, but extensive sequence homology is not required (Toffolatti et al., 2002).”

• cites Toffolatti et al., 2002 sourceNot checked yet

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Despite high heritability, the genetic basis of ASDs is complex.

“Despite high heritability, the genetic basis of ASDs is complex.”

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Heritability estimates for ASD from clinically ascertained twin samples range widely from 38% to 90%, but genes play a major role.

“Heritability estimates based on studies of clinically ascertained twin samples (Bailey et al., 1995; Folstein and Rutter, 1977; Hallmayer et al., 2011; Steffenburg et al., 1989) vary widely, from 38% to 90%, but it is clear that genes play a major role in ASD.”

• cites Bailey et al., 1995 sourceNot checked yet

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• cites Folstein and Rutter, 1977 sourceNot checked yet

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• cites Hallmayer et al., 2011 sourceNot checked yet

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Current genotyping platforms and CNV discovery algorithms can genotype about 1,000 common copy-number polymorphisms and discover additional novel CNVs, including rare or individual-specific mutations.

“Current genotyping platforms and CNV discovery algorithms enable the genotyping of ~1000 common copy number polymorphisms (CNPs) and the discovery of additional “novel” CNVs, including mutations that are rare or unique to an individual (Alkan et al., 2011).”

• cites Alkan et al., 2011 sourceNot checked yet

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The genome-wide rate of nucleotide substitutions is estimated at 30-100 per generation, with about one per exome.

“The rate of nucleotide substitutions genome-wide is estimated at 30–100 per generation (Conrad et al., 2011) and ~1 per exome.”

• cites Conrad et al., 2011 sourceNot checked yet

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Early twin studies found 80-90% concordance for ASDs in monozygotic twins and 5-15% concordance in dizygotic twins and siblings.

“Early twin studies observed 80–90% concordance for ASDs in monozygotic (MZ) twins and 5–15% concordance in dizygotic (DZ) twins and siblings.”

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In large ASD simplex cohorts, rare de novo CNV burden is significantly greater in simplex cases (5.8-7.9%) than unaffected siblings (1.7-1.9%) in total events, event size, and gene content.

“These studies reported that the burden of rare de novo CNVs is significantly greater in simplex cases (5.8–7.9%) than in unaffected siblings (1.7–1.9%) with regard to the total number of events, the size of each event, and their gene content.”

• cites Levy et al., 2011 sourceNot checked yet

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• cites Sanders et al., 2011 sourceNot checked yet

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Levy et al. estimated about 250-300 target loci for ASDs, and Sanders et al. estimated 130-234 loci.

“Based on the number of recurrent de novo CNVs and the estimated proportion of de novo CNVs ascertained, Levy et al estimated around 250–300 target loci for ASDs and Sanders et al. estimated between 130–234 loci.”

• cites Levy et al., 2011 sourceNot checked yet

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• cites Sanders et al., 2011 sourceNot checked yet

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Two recent studies report higher dizygotic twin concordance (31%), suggesting that shared environmental factors may contribute more than previously estimated.

“Two recent studies report somewhat higher rates of concordance in DZ twins (31%), suggesting, that the contribution of shared environmental factors could be greater than had been previously estimated (Hallmayer et al., 2011; Rosenberg et al., 2009).”

• cites Hallmayer et al., 2011 sourceNot checked yet

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• cites Rosenberg et al., 2009 sourceNot checked yet

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CNVs as a class, and de novo CNVs especially, are expected to be enriched for variants with large effects on disease risk.

“Thus, we expect that CNVs as a class, and de novo CNVs in particular, will be more enriched in variants that have large effect on disease risk.”

May combine two claims.

Subsequent larger studies confirmed a high rate (5-10%) of de novo CNVs in ASD and further clarified the extent of genetic heterogeneity.

“Subsequent studies in larger samples have confirmed a high (5–10%) rate of de novo CNVs in ASD and further elucidated the extent of genetic heterogeneity in ASD (Itsara et al., 2010; Levy et al., 2011; Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011).”

• cites Itsara et al., 2010 sourceNot checked yet

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• cites Levy et al., 2011 sourceNot checked yet

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• cites Marshall et al., 2008 sourceNot checked yet

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By number, nucleotide substitutions probably account for most disease risk alleles, but structural mutations are more pathogenic on average because of their size and potential to affect genes.

“Based on sheer numbers, nucleotide substitutions probably account for the majority of disease risk alleles, but based on sheer size and potential to impact genes (or multiple genes), structural mutations are more pathogenic on average.”

May combine two claims.

Some non-recurrent deletion CNVs have 2-20 bp of microhomology at their breakpoints and are predicted to arise through MMEJ.

“Breakpoints of some non-recurrent deletion CNVs have sequences with very short (2–20 basepairs) stretches of nucleotide identity. These are predicted to be formed by an alternative microhomology mediated end joining (MMEJ) mechanism (Lieber, 2010).”

• cites Lieber, 2010 sourceNot checked yet

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Affected ASD cases had on average a 16-fold excess of genes affected by de novo CNVs compared with healthy siblings, and a 30-fold excess for deletions.

“Affected cases on average had 16-fold excess of genes impacted by de novo CNVs compared to healthy sibs (30-fold for deletions).”

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Large cytogenetically detectable chromosomal abnormalities, including maternal 15q11-13 duplication and 22q11.2 microdeletion, occur recurrently in small proportions of idiopathic autism and schizophrenia, respectively.

“In addition, large cytogenetically-detectable chromosomal abnormalities, including maternally inherited duplication of chromosome 15q11-13 and microdeletions of 22q11.2, were also known to occur recurrently in a small proportion of idiopathic autism cases (Gillberg, 1998) and in schizophrenia (Murphy et al., 1999) respectively.”

• cites Gillberg, 1998 sourceNot checked yet

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• cites Murphy et al., 1999 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

FoSTeS is a replication-based rearrangement mechanism triggered by single-strand breaks during DNA replication.

“FoSTeS is a replication-based genomic rearrangement mechanism that is induced by errors (single strand breaks) during DNA replication process (Lee et al., 2007).”

• cites Lee et al., 2007 sourceNot checked yet

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Pathway analyses have found ASD CNV enrichment in ubiquitin pathways, cellular proliferation/projection/motility and GTPase/Ras signaling, and synapse development/axon targeting/neuron motility.

“Glessner et al. (2009) observed an enrichment of CNVs at multiple sites, and some of their top hits were genes involved in ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40. Pinto et al. (2010) observed an enrichment of CNVs within gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signaling. Gilman et al. (2011) found an enrichment of CNVs in gene”

• cites Glessner et al., 2009 sourceNot checked yet

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• cites Pinto et al., 2010 sourceNot checked yet

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• cites Gilman et al., 2011 sourceNot checked yet

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Xu et al. observed a high rate of de novo CNVs in sporadic schizophrenia cases (10%) compared with familial cases and controls.

“In the first systematic study of de novo CNVs in schizophrenia, Xu et al. observed a high rate in sporadic cases (10%) as compared with “familial” cases (defined as having an affected first or second degree relative) and a high rate compared with controls (Xu et al., 2008).”

• cites Xu et al., 2008Not checked yet

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In the Autism Genome Project case-control study, 996 ASD individuals of European ancestry had a higher global burden of rare genic CNVs than 1,287 matched controls (1.19-fold, P = 0.012), especially in regions previously implicated in ASD and/or intellectual disability (1.69-fold, P = 3.4 × 10−4).

“When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for genomic regions previously implicated in ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10−4).”

• cites Pinto et al., 2010 sourceNot checked yet

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The most frequent recurrent CNVs in ASD tend to be large (>500 kb) and contain multiple genes.

“The most frequent recurrent CNVs tend to be large (>500 kb) and contain multiple genes.”

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Rare or de novo CNVs smaller than 100 kb sometimes disrupt a single gene, but strong statistical evidence for them is lacking.

“Rare or de novo CNVs have been identified that are smaller (<100 Kb) in size, sometimes disrupting a single gene, but strong statistical evidence is lacking.”

May combine two claims.

Two studies reported enrichment of rare CNVs in bipolar disorder, with the greatest effect in early age-at-onset subjects, but the effects were small (OR ~1.5).

“Two studies have reported an enrichment of rare CNVs in bipolar disorder (Priebe et al., 2011; Zhang et al., 2009a). In both studies, the observed effect was greatest in subjects with an early age-at-onset. However, the observed effects were still quite small (OR~1.5)”

• cites Priebe et al., 2011Not checked yet

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• cites Zhang et al., 2009aNot checked yet

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Recent genome-wide studies found strong evidence of association with schizophrenia for deletions at 1q21.1, 3q29, and 15q13.3, exonic NRXN1 deletions, and duplications at 16p11.2 and 7q36.3 (VIPR2).

“Recent genome-wide studies have found strong evidence of association for other loci including deletions at chr1q21.1, deletions at chr3q29, duplications of chr16p11.2, deletions at chr15q13.3, exonic deletions at chr2p16.3 (NRXN1) and duplications at chr7q36.3 (VIPR2), with schizophrenia (Table 1; Supplemental Information).”

• cites Table 1Not checked yet

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Kirov et al. and Malhotra et al. observed a high rate of de novo CNVs in schizophrenia (5% in both) compared with controls, but neither found a significant difference between sporadic and familial cases.

“Subsequent studies by Kirov et al. (Kirov et al., 2011) and by our group (Malhotra et al., 2011), also observed a high rate of de novo CNVs in schizophrenia (5% in both studies) as compared with controls; however, neither study observed a significant difference in rate between in sporadic and famial cases.”

• cites Kirov et al., 2011Not checked yet

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• cites Malhotra et al., 2011 sourceNot checked yet

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Sanders et al. independently replicated the CNV burden finding when rare transmitted and de novo CNVs were included, but significant enrichment was not observed exclusively among inherited variants.

“These findings were independently replicated by Sanders et al (Sanders et al., 2011), when CNV burden analysis included both rare transmitted and de novo CNVs; however, a significant enrichment of CNVs was not observed exclusively among variants that were inherited (Levy et al., 2011; Sanders et al., 2011).”

• cites Sanders et al., 2011 sourceNot checked yet

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• cites Levy et al., 2011 sourceNot checked yet

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Current evidence suggests CNVs have a role in bipolar disorder, but large deletions in particular play a very limited role.

“Current evidence suggests that CNVs have a role to play (Malhotra et al., 2011), but some, particularly large deletions appear to play a very limited role (Grozeva et al., 2010; Malhotra et al., 2011).”

• cites Malhotra et al., 2011 sourceNot checked yet

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• cites Grozeva et al., 2010 sourceNot checked yet

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A prior study found that familial segregation of early-onset bipolar disorder was consistent with major gene effects, while late-onset segregation was consistent with multifactorial etiology.

“Also consistent with this notion, a previous study found that segregation of early-onset bipolar disorder in families was consistent with major gene effects, whereas familial segregation of late-onset bipolar disorder was consistent with a multifactorial etiology (Grigoroiu-Serbanescu et al., 2001).”

• cites Grigoroiu-Serbanescu et al., 2001 sourceNot checked yet

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De novo mutation offers a possible explanation for the lack of mendelian consistency in family studies and for the discrepancy between high monozygotic and low dizygotic twin concordance rates.

“De novo mutation offers a possible explanation for the lack of mendelian consistency observed in family studies and the discrepancy between high monozygotic and low dizygotic twin concordance rates (Zhao et al., 2007).”

• cites Zhao et al., 2007 sourceNot checked yet

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Mice with a paternal duplication of 15q11-13 display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety.

“Mice with a paternal duplication of 15q11-13 display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety (Nakatani et al., 2009).”

• cites Nakatani et al., 2009 sourceNot checked yet

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When key CNV observations are considered, a rare variant model is now plausible and consistent with the genetic data.

“When we take into consideration some key observations of CNV studies, a rare variant model is now plausible and consistent with the genetic data.”

• AssumptionRests on an assumption: Family data did not appear to be consistent with major gene effects.

May combine two claims.

Some CNV alleles have no association with intellectual disability, or a relatively weak one compared with their association with psychiatric phenotypes.

“Some CNV alleles have no association with intellectual disability (e.g. 17p12/HNPP) or a relatively weak one compared with the association with psychiatric phenotypes (e.g., microduplications of 1q21.1 and 16p11.2), see Table 1.”

• cites Table 1Not checked yet

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Reciprocal deletion and duplication of 16p11.2 result in similar brain structural alterations in human and mouse, with deletion associated with brain overgrowth and duplication with reduced brain volume.

“For example reciprocal deletion and duplication of 16p11.2 result in similar brain structural alterations in human and mouse, the deletion associated with brain overgrowth and the duplication associated with reduced brain volume (Horev et al., 2011; McCarthy et al., 2009; Shinawi et al., 2010), and structural alterations appear to be widely distributed across multiple brain regions.”

• cites Horev et al., 2011 sourceNot checked yet

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• cites McCarthy et al., 2009 sourceNot checked yet

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• cites Shinawi et al., 2010 sourceNot checked yet

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Mice lacking Cntnap2 display deficits in social interaction and communication, hyperactivity, and seizures.

“Mice lacking Contactin-associated protein 2 (Cntnap2) display deficits in social interaction and communication, hyperactivity, and seizures (Penagarikano et al., 2011).”

• cites Penagarikano et al., 2011 sourceNot checked yet

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16p11.2 microduplications are associated with autism, schizophrenia, or bipolar disorder.

“Likewise microduplications of 16p11.2 are associated with autism, schizophrenia or bipolar disorder (McCarthy et al., 2009; Weiss et al., 2008).”

• cites McCarthy et al., 2009 sourceNot checked yet

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• cites Weiss et al., 2008 sourceNot checked yet

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Reciprocal rearrangements of 1q21.1 and 16p11.2 influence neuropsychiatric traits, susceptibility to epilepsy, and head size in humans.

“For instance, reciprocal rearrangements of 1q21.1 and 16p11.2 influence neuropsychiatric traits, susceptibility to epilepsy and head size in humans.”

May combine two claims.

Intellectual disability is itself highly variable and does not appear to be a primary characteristic for a number of disease-associated CNVs.

“Intellectual disability is itself a highly variable trait, and does not appear to be a primary characteristic for a number of disease-associated CNVs.”

May combine two claims.

Mice lacking neurexin-1α display decreased pre-pulse inhibition, increased grooming, impaired nest-building, and improved motor learning.

“Mice lacking neurexin-1α display a decrease in pre-pulse inhibition, an increase in grooming behaviors, impairment in nest-building activity, and an improvement in motor learning (Etherton et al., 2009).”

• cites Etherton et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

A model attributes phenotypic variability to a combination of locus heterogeneity and pleiotropic effects of individual alleles.

“Another model has been proposed that attributes phenotypic variability to a combination of locus heterogeneity and pleiotropic effects of the individual alleles (State and Levitt, 2011).”

• cites State and Levitt, 2011 sourceNot checked yet

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Neuroanatomical features are more analogous between model organisms and humans than behavior, and the neuroanatomical effects of CNVs might be as well.

“Compared to behavior, neuroanatomical features are more analogous between model organisms and human, and the neuroanatomical effects of CNVs might be as well.”

May combine two claims.

The degree of risk conferred for a psychiatric disorder is related to specific genes within the CNV region and to how changes in gene dosage influence neurodevelopment.

“These observations suggest that the degree of risk conferred for a psychiatric disorder is related to specific genes within the CNV region and how changes in gene dosage influence neurodevelopment.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A rare variant/heterogeneity model of common disease and its negative implications for GWAS had been acknowledged as a possibility early on.

“A rare variant/heterogeneity model of common disease and its negative implications for GWAS had been acknowledged as a possibility early on (Reich and Lander, 2001).”

• cites Reich and Lander, 2001Not checked yet

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A single target might contribute genetic risk to less than 1% of patients, and a compound active against a single target might benefit only patients with that mutation.

“A single target might contribute genetic risk to only a small fraction (<1%) of patients, and a compound active against a single target might benefit only patients with that mutation.”

May combine two claims.

Schizophrenia hiPSC-derived neurons had significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic PSD95 levels, and altered gene expression profiles.

“Schizophrenia-hiPSC-derived neurons had significantly reduced neuronal connectivity, reduced neurite outgrowth, reduced dendritic levels of PSD95, and altered gene expression profiles.”

• cites Brennand et al., 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

These efforts are accompanied by ongoing CNV studies of the same cohorts, and will be well powered to capture additional risk genes.

“These efforts are accompanied by ongoing CNV studies of the same cohorts, and will be well powered to capture additional risk genes.”

Classified as probably not a substantial claim.

Large-scale studies are underway through international efforts including the Psychiatric Genomics Consortium and the Wellcome Trust Case Control Consortium.

“Such large scale studies are underway through International efforts including by the Psychiatric Genomics Consortium (PGC) (Ripke et al., 2011) and Wellcome Trust Case Control Consortium (WTCCC).”

• cites Ripke et al., 2011 sourceNot checked yet

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Early hiPSC studies provide clues into the neurobiological processes underlying schizophrenia, but without information on genetic contributors in these patients, a clear mechanistic understanding is lacking.

“These early studies provide clues into the neurobiological processes that underlie schizophrenia, but without information on the genetic contributors in these patients, a clear mechanistic understanding is lacking.”

May combine two claims.

The majority of risk variants are non-recurrent mutations with lower mutation rates and lower frequencies, and will require larger studies to unequivocally demonstrate association with disease.

“The majority are non-recurrent mutations, which have lower mutation rates and lower frequencies and will require larger studies to unequivocally demonstrate an association with disease.”

May combine two claims.

Human mutations in the Timothy Syndrome gene Cav1.2 influence calcium signaling and the differentiation of cortical neurons.

“Pasca et al (2011) showed that human mutations in the Timothy Syndrome gene Cav1.2 influence calcium signaling and the differentiation of cortical neurons, and the observed defects on calcium (Ca2+) signaling were reversible with the L-type calcium channel blocker roscovitine.”

• cites Pasca et al., 2011 sourceNot checked yet

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Classified as probably not a substantial claim.

Drug discovery for neuropsychiatric diseases could involve developing a catalogue of drugs targeting a variety of orphan diseases.

“Hence, drug discovery for neuropsychiatric diseases could involve developing a catalogue of drugs targeting a variety of orphan diseases (Braun et al., 2010).”

• cites Braun et al., 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Success will increasingly depend on integrating signals from de novo, inherited, common, and rare forms of genomic variation.

“However, as we move ahead, success will increasingly depend on our ability to integrate the signal from de novo, inherited, common, and rare forms of variation in the genome.”

Probably not a substantial claim: may not pass S2 (checkable).

A growing body of CNV research provides a compelling rationale for undertaking a complementary sequencing approach to psychiatric disease.

“A growing body of research on CNV provides a compelling rationale for undertaking a complementary sequencing approach to psychiatric disease.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

One target gene might represent one component of a pathway that is dysregulated in a larger proportion of cases.

“More optimistically, one target gene might represent one component of a pathway that is dysregulated in a larger proportion of cases.”

May combine two claims.

Mice lacking Shank3 have defects in striatal synapses and cortico-striatal circuits.

“Mice lacking Shank3 have defects in striatal synapses and cortico-striatal circuits (Peca et al., 2011).”

• cites Peca et al., 2011 sourceNot checked yet

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Cultured neurons from humans with Rett Syndrome MeCP2 mutations had fewer synapses, reduced spine density, smaller soma size, reduced intracellular calcium response, and decreased frequency and amplitude of spontaneous excitatory and inhibitory postsynaptic currents.

“Marchetto et al (Marchetto et al., 2010) showed that cultured neurons derived from humans with mutations in the Rett Syndrome gene MeCP2 had fewer synapses, reduced spine density, smaller soma size, and exhibited a reduction in the intracellular calcium response and decrease in the frequency and amplitude of spontaneous excitatory and inhibitory postsynaptic currents.”

• cites Marchetto et al., 2010 sourceNot checked yet

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Disease-associated VIPR2 variants result in overexpression of VIPR2 and increased cyclic-AMP accumulation.

“Disease associated variants result in overexpression of VIPR2 and increased cyclic-AMP accumulation (Vacic et al., 2011).”

• cites Vacic et al., 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

Genetic testing has not yet been established as the nationwide standard of care for ASD, schizophrenia, or bipolar disorder.

“However, genetic testing has not yet been established as the nationwide standard of care for ASD, schizophrenia or bipolar disorder.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Success in psychiatric genetics will depend on statistical power and sample size.

“As always, success will depend on statistical power and sample size.”

May combine two claims.

These hotspots represent the largest and most pathogenic risk alleles.

“These represent the largest and most pathogenic risk alleles.”

May combine two claims.

In studies of de novo CNV, hotspots represent 25% of mutations and thus probably represent a minority of risk variants.

“However, in studies of de novo CNV these hotspots represent 25% of mutations and thus, probably represent a minority of the risk variants.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Patient-derived neuronal cell cultures capture the complete set of risk alleles in the patient germline and the genetic diversity of the patient population, unlike genetically engineered model systems.

“Unlike genetically-engineered model systems, neuronal cell cultures derived from patients captures the complete set of risk alleles present in the patient germline and the genetic diversity of the patient population.”

May combine two claims.

Mice lacking Cntnap2 exhibit neuronal migration abnormalities, reduced numbers of interneurons, and abnormal neuronal network activity.

“Mice lacking Cntnap2 exhibit neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity (Penagarikano et al., 2011).”

• cites Penagarikano et al., 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Genetic approaches that have worked well for CNVs should adapt well to sequencing platforms.

“Genetic approaches that have worked well for CNVs (Figure 3) should adapt well to sequencing platforms.”

• cites Figure 3Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

High-throughput sequencing efforts are currently under way to sequence exomes and whole genomes in all major psychiatric disorders.

“The era of high-throughput sequencing is now in full swing, with efforts currently under way to sequence exomes and whole genomes in all major psychiatric disorders (Girard et al., 2011; Najmabadi et al., 2011; O’Roak et al., 2011; Vissers et al., 2010; Xu et al., 2011).”

• cites Girard et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites Najmabadi et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites O’Roak et al., 2011Not checked yet

  Not checked in the free run.