Genetic architectures of psychiatric disorders: the emerging picture and its implications

In the paper

“The proportion of variance explained by the risk profile score increased with relaxation of the significance thresholds.”

What the sources say

• Not checked yetcites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

In the paper

“As an important test of specificity, the SCZ risk profile was not predictive of case status for any of six non-psychiatric diseases. 177”

What the sources say

• Not checked yetcites [177] The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). source

In the paper

“In three independent GWAS, SCZ cases had significantly higher risk profile scores than controls.”

What the sources say

• Not checked yetcites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

In the paper

“A novel association for SCZ is in Ensembl gene RP11-490G2.1 which encodes the primary transcript for miR-137 (MIR137). 62”

What the sources say

• Not checked yetcites [62] Zhong, L., Cherry, T., Bies, C. E., Florence, M. A. & Gerges, N. Z. Neurogranin enhances synaptic strength through its interaction with calmodulin. EMBO J. 28, 3027–3039 (2009). source

In the paper

“For SCZ, the strongest association is in the extended MHC region (chr6:27–33 Mb).”

In the paper

“Karyotyping studies suggested that on the order of 5% of ASD cases have one of a large number of rare but relatively gross chromosomal abnormalities. 14,78”

What the sources say

• Not checked yetcites [14] Vorstman, J. A. et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol. Psychiatry 11, 18–28 (2006). source
• Not checked yetcites [78] Stahl, E. A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nature Genet. 44, 483–489 (2012). source

In the paper

“Combined analysis of the PGC BIP and SCZ samples strengthened the association in the CACNA1C region.”

In the paper

“Indeed, multiple voltage gated calcium channel subunits were among the top 34 loci followed up in the BIP GWAS.”

In the paper

“Unexpectedly, simplex and multiplex ASD pedigrees show relatively similar de novo mutation rates for SV 80,81 and exonic variation. 83–85”

What the sources say

• Not checked yetcites [80] Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011). source
• Not checked yetcites [81] Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011). There have been many excellent studies of CNVs in autism. This is one of the largest and is particularly technically well done. The authors report compelling findings regarding specific CNVs and a greater burden of rare CNVs in cases with ASD. source
• Not checked yetcites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source
• Not checked yetcites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source
• Not checked yetcites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

In the paper

“The PGC GWAS mega-analysis of 9,240 MDD cases and 9,519 controls (replication in 6,783 MDD cases) revealed no findings of genome-wide significance. 108”

What the sources say

• Not checked yetcites [108] Fowler, C. D., Lu, Q., Johnson, P. M., Marks, M. J. & Kenny, P. J. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471, 597–601 (2011). source

In the paper

“This association did not replicate in an independent but similar study from the same geographic region, casting particular doubt on the reported association. 115”

What the sources say

• Not checked yetcites [115] Risch, N. et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301, 2462–2471 (2009). source

In the paper

“The genetic findings now strongly point to the former.”

In the paper

“Since 2007, numerous robust and replicable genetic findings have been reported for psychiatric disorders.”

What the sources say

• Not checked yetcites [6] Chanock, S. J. et al. Replicating genotype–phenotype associations. Nature 447, 655–660 (2007). source

In the paper

“Intriguingly, pathway analyses (Box 2) of AD implicate cholesterol metabolism and the innate immune response. 38”

What the sources say

• Not checked yetcites [38] Jones, L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5, e13950 (2010). source

In the paper

“However, rare (frequency < 0.5%) but potent (genotypic relative risk, GRR, 5–20) SVs play a role in a small proportion of cases with SCZ (Table 2, Figure S1).”

In the paper

“These estimates suggest that “missing heritability” is merely hidden and imperfectly assayed by current genotyping technologies.”

In the paper

“Increased SV burden in SCZ cases has been reported by multiple groups. 47,48,50”

What the sources say

• Not checked yetcites [47] Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008). source
• Not checked yetcites [48] International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008). source
• Not checked yetcites [50] Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008). source

In the paper

“De novo SV are also more common in SCZ cases. 45”

What the sources say

• Not checked yetcites [45] Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2011). source

In the paper

“For SCZ and BIP, sign tests comparing the consistency of association tests from discovery GWAS and replication samples for sets of top signals are usually highly significant even if most loci do not meet genome-wide significance. 58,59,174”

What the sources say

• Not checked yetcites [58] Need, A. C. et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am. J. Hum. Genet. (in the press). In the largest study yet reported, the authors report exome resequencing of 166 cases with schizophrenia enriched for strong family histories of illness and treatment non-response. No definitive associations were identified: this intriguing finding makes the 'many Mendelians' model of this disorder far less tenable.
• Not checked yetcites [59] Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genet. 43, 969–976 (2011). source
• Not checked yetcites [174] O'Donovan, M. et al. Identification of novel schizophrenia loci by genome-wide association and follow-up. Nature Genet. 40, 1053–1055 (2008). source

In the paper

“For ASD there is a notably strong prima facie case for there being a a cardinal role for rare variation.”

In the paper

“There is also consistent evidence for increased SV burden in ASD. 49,80–82”

What the sources say

• Not checked yetcites [49] Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007). source
• Not checked yetcites [80] Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011). source
• Not checked yetcites [81] Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011). There have been many excellent studies of CNVs in autism. This is one of the largest and is particularly technically well done. The authors report compelling findings regarding specific CNVs and a greater burden of rare CNVs in cases with ASD. source
• Not checked yetcites [82] Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010). source

In the paper

“Indeed, the large-scale impact of large numbers of common variants may be a general feature of human complex traits 70–77”

What the sources say

• Not checked yetcites [70] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source
• Not checked yetcites [71] Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012). source
• Not checked yetcites [72] Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genet. 42, 579–589 (2010). source
• Not checked yetcites [73] Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010). source
• Not checked yetcites [74] Houlston, R. S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nature Genet. 42, 973–977 (2010). source
• Not checked yetcites [75] Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nature Genet. 42, 504–507 (2010). source
• Not checked yetcites [76] Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). source
• Not checked yetcites [77] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010). source

In the paper

“Three recent papers describe the results from exome sequencing of ~600 trios, and identify roles for de novo exonic mutations in SCN2A, KATNAL2, and CHD8 in the pathogenesis of ASD. 83–85”

What the sources say

• Not checked yetcites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source
• Not checked yetcites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source
• Not checked yetcites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

In the paper

“However, a central finding from these papers was that only a minority of cases had a de novo putatively functional variant”

What the sources say

• Not checked yetcites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source
• Not checked yetcites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source
• Not checked yetcites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

In the paper

“estimates from de novo exonic mutations (similar to those from SV data) suggest that ASD is highly polygenic (estimates ranged from 400–1000 genes). 84,85”

What the sources say

• Not checked yetcites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source
• Not checked yetcites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

In the paper

“pathway analyses reported in two of the studies found that genes containing de novo exonic variation were more closely connected in reference to protein-protein interaction databases. 83,84”

What the sources say

• Not checked yetcites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source
• Not checked yetcites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source

In the paper

“For SCZ, the available data are insufficient to resolve this issue. 45,50”

What the sources say

• Not checked yetcites [45] Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2011). source
• Not checked yetcites [50] Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genet. 40, 880–885 (2008). source

In the paper

“suggesting that this class of genetic variation is unlikely fully to explain the clinical entity of ASD.”

In the paper

“It is currently not possible to discern or dismiss a role for common genetic variation in risk for ASD.”

In the paper

“Using a candidate gene approach, the association of ADH1B with ALC and alcohol consumption was extended to European ancestry subjects. 101”

What the sources say

• Not checked yetcites [101] Schumann, G. et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc. Natl Acad. Sci. USA 108, 7119–7124 (2011). source

In the paper

“The strongest finding is an association of smoking quantity with a cluster of nicotinic receptor genes (CHRNA5-CHRNA3-CHRNB4) with an effect size corresponding to one cigarette per day, and there may be several independent associations. 104”

What the sources say

• Not checked yetcites [104] Liu, J. Z. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature Genet. 42, 436–440 (2010). source

In the paper

“Importantly, a hypothetical model of ASD caused by rare but fully penetrant mutations in 100 different genes could be confidently rejected. 83”

What the sources say

• Not checked yetcites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source

In the paper

“and AUTS2 was implicated in alcohol consumption in European subjects. 100”

What the sources say

• Not checked yetcites [100] Takeuchi, F. et al. Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ. J. 75, 911–918 (2011). source

In the paper

“A recent study showed that Chrna5 null mice had higher nicotine intake due to loss of an inhibitory effect on brain reward systems. 107”

What the sources say

• Not checked yetcites [107] Truong, T. et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J. Natl Cancer Inst. 102, 959–971 (2010). source

In the paper

“given that detailed studies of rare variation currently explain a fraction of risk”

In the paper

“particularly given that risk profile analysis (Box 3) suggested that larger samples would yield more associations. 97”

What the sources say

• Not checked yetcites [97] Heath, A. C. et al. A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biol. Psychiatry 70, 513–518 (2011). source

In the paper

“The strongest finding is an association of smoking quantity with a cluster of nicotinic receptor genes (CHRNA5-CHRNA3-CHRNB4) with an effect size corresponding to one cigarette per day, and there may be several independent associations. 104”

What the sources say

• Not checked yetcites [104] Liu, J. Z. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature Genet. 42, 436–440 (2010). source

In the paper

“Evaluation of rare SV and exonic variation in ASD is particularly advanced. In contrast, evaluation of common variation is far more limited (Figure 1a)”

In the paper

“the published GWAS for ASD are small by current standards. 86–89”

What the sources say

• Not checked yetcites [86] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). These three papers report exome sequencing of trios with ASD. Support was found for 2–4 de novo mutations that are plausibly causal. However, as for schizophrenia (reference 58), an abundance of Mendelian variants was not identified. source
• Not checked yetcites [87] Wang, K. et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528–533 (2009). source
• Not checked yetcites [88] Weiss, L. A., Arking, D. E., Daly, M. J. & Chakravarti, A. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461, 802–808 (2009). source
• Not checked yetcites [89] Anney, R. et al. A genome-wide scan for common alleles affecting risk for autism. Hum. Mol. Genet. 19, 4072–4082 (2010). source

In the paper

“Indeed, there were few confident findings for GWAS of SCZ when the sample sizes were similar to those now available for ASD.”

In the paper

“For alcohol consumption, GWAS in East Asian samples confirmed the role of ALDH2, 98,99”

What the sources say

• Not checked yetcites [98] Frank, J. et al. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict. Biol. 17, 171–180 (2012). source
• Not checked yetcites [99] Baik, I., Cho, N. H., Kim, S. H., Han, B. G. & Shin, C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am. J. Clin. Nutr. 93, 809–816 (2011). source

In the paper

“Meta-analyses have supported 111,112 and not supported 113,114 this finding.”

What the sources say

• Not checked yetcites [111] Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003). source
• Not checked yetcites [112] Karg, K., Burmeister, M., Shedden, K. & Sen, S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch. Gen. Psychiatry 68, 444–454 (2011). source

In the paper

“There are few published data on SV although one study found increased SV burden in MDD cases versus controls (OR=1.31). 109”

What the sources say

• Not checked yetcites [109] Major Depressive Disorder Working Group of the PGC. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 3 Apr 2012 (doi:10.1038/mp.2012.21). Despite a heritability and lifetime prevalence that is not dissimilar to T2DM and in contrast to similarly sized studies of BIP and SCZ, this study of MDD is largely negative. Higher heterogeneity is a prime candidate for the divergent results.

In the paper

“This association did not replicate in an independent but similar study from the same geographic region, casting particular doubt on the reported association. 115”

In the paper

“In ADHD, increased SV burden has been reported (OR=2.1), 118,119”

What the sources say

• Not checked yetcites [118] Wang, K. et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol. Psychiatry 16, 949–959 (2011). source
• Not checked yetcites [119] Williams, N. M. et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 376, 1401–1408 (2010). source

In the paper

“Given low power, no conclusions about common variation can be made.”

In the paper

“Meta-analyses have supported 111,112 and not supported 113,114 this finding.”

What the sources say

• Not checked yetcites [113] Uher, R. & McGuffin, P. The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Mol. Psychiatry 15, 18–22 (2010). source
• Not checked yetcites [114] Munafo, M. R., Durrant, C., Lewis, G. & Flint, J. Gene X environment interactions at the serotonin transporter locus. Biol. Psychiatry 65, 211–219 (2009). source

In the paper

“Thus, it appears that the reason no common variants have yet confidently been implicated in ADHD by GWAS is lack of power, not lack of variants to be found.”

In the paper

“Pathway analysis in ADHD found association signals enriched in the same GO categories also overrepresented for large SV. 120”

What the sources say

• Not checked yetcites [120] Williams, N. M. et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am. J. Psychiatry 169, 195–204 (2012). source

In the paper

“an effect higher in ADHD cases with MR (OR=5.7). 118”

What the sources say

• Not checked yetcites [118] Wang, K. et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol. Psychiatry 16, 949–959 (2011). source

In the paper

“The weak signals in ADHD GWAS are not randomly distributed but index the same pathophysiological pathways as rare SV.”

What the sources say

• Not checked yetcites [120] Williams, N. M. et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am. J. Psychiatry 169, 195–204 (2012). source

In the paper

“Knowledge of psychiatric genetics is vastly greater than it was five years ago.”

In the paper

“Hypothesized genetic architectures consisting entirely of rare variants are inconsistent with the data for AD, ASD, BIP, and SCZ (as well as for multiple other complex biomedical diseases). 70–77”

What the sources say

• Not checked yetcites [70] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source
• Not checked yetcites [71] Visscher, P. M., Brown, M. A., McCarthy, M. I. & Yang, J. Five years of GWAS discovery. Am. J. Hum. Genet. 90, 7–24 (2012). source
• Not checked yetcites [72] Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genet. 42, 579–589 (2010). source
• Not checked yetcites [73] Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010). source
• Not checked yetcites [74] Houlston, R. S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nature Genet. 42, 973–977 (2010). source
• Not checked yetcites [75] Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nature Genet. 42, 504–507 (2010). source
• Not checked yetcites [76] Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). source
• Not checked yetcites [77] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010). source

In the paper

“The Procrustean theory that common variant signals inevitably reflect “synthetic associations” 124 to rare, high penetrance mutations is not credible. 77,125–127”

What the sources say

• Not checked yetcites [77] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010). source
• Not checked yetcites [125] Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D. B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010). source
• Not checked yetcites [126] Wray, N. R., Purcell, S. M. & Visscher, P. M. Synthetic associations created by rare variants do not explain most GWAS results. PLoS Biol. 9, e1000579 (2011). source
• Not checked yetcites [127] Anderson, C. A., Soranzo, N., Zeggini, E. & Barrett, J. C. Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol. 9, e1000580 (2011). source

In the paper

“Psychiatric disorders are polygenic.”

In the paper

“Polygenicity may be a general feature of complex biomedical diseases. 128,129”

What the sources say

• Not checked yetcites [128] Orozco, G., Barrett, J. C. & Zeggini, E. Synthetic associations in the context of genome-wide association scan signals. Hum. Mol. Genet. 19, R137–R144 (2010). source
• Not checked yetcites [129] Lander, E. S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011). source

In the paper

“The evidence is strong that many genes are involved in the etiology of AD (currently evidence of rare exonic, rare SV, and common variation), ALC (currently evidence of common variation), ASD (currently evidence of de novo exonic variation and SV), BIP (currently evidence of common variation), NIC (currently evidence of common variation), and SCZ (currently evidence of rare SV and common variation”

In the paper

“Projections for ASD and SCZ suggest that variation at hundreds of different genes will ultimately be shown to be involved. 58,80,85”

What the sources say

• Not checked yetcites [58] Need, A. C. et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am. J. Hum. Genet. (in the press). In the largest study yet reported, the authors report exome resequencing of 166 cases with schizophrenia enriched for strong family histories of illness and treatment non-response. No definitive associations were identified: this intriguing finding makes the 'many Mendelians' model of this disorder far less tenable.
• Not checked yetcites [80] Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011). source
• Not checked yetcites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

In the paper

“These results are consistent with suggestions that the “missing heritability” 133 is merely hidden. 132”

What the sources say

• Not checked yetcites [132] Davies, G. et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol. Psychiatry 16, 996–1005 (2011). source

In the paper

“currently we do not now possess a comprehensive enumeration of loci associated with any psychiatric disorder (i.e., the “parts list”), regardless of where genetic variation might lie in the allelic spectrum-effect size space.”

In the paper

“For this primary goal, there have been unequivocal successes for many psychiatric disorders.”

In the paper

“Most discoveries in psychiatric genetics to date are from GWAS and SV evaluation (both often based on the use of GWAS chips)”

In the paper

“For SCZ, this conceptualization is supported by the risk profile findings for SCZ, and by the miR-137 results that hint at an underlying regulatory network.”

In the paper

“For ASD, typical patterns of cortical gene expression in frontal and temporal cortex have been found to be attenuated in ASD cases compared to controls”

What the sources say

• Not checked yetcites [90] Ma, D. et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73, 263–273 (2009). source

In the paper

“and an empirically-derived gene expression module that is under-expressed in ASD was found to be enriched for known ASD susceptibility genes and genetic association signals. 90”

What the sources say

• Not checked yetcites [90] Ma, D. et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73, 263–273 (2009). source

In the paper

“historically, psychiatric research has ben underfunded in comparison to public health impact (with the possible exception of AD). 141–144”

What the sources say

• Not checked yetcites [141] Yang, J., Wray, N. R. & Visscher, P. M. Comparing apples and oranges: equating the power of case–control and quantitative trait association studies. Genet. Epidemiol. 34, 254–257 (2010). source
• Not checked yetcites [142] Gross, C. P., Anderson, G. F. & Powe, N. R. The relation between funding by the National Institutes of Health and the burden of disease. New Engl. J. Med. 340, 1881–1887 (1999). source
• Not checked yetcites [143] Aoun, S., Pennebaker, D. & Pascal, R. To what extent is health and medical research funding associated with the burden of disease in Australia? Aust. N. Z. J. Public Health 28, 80–86 (2004). source
• Not checked yetcites [144] Gillum, L. A. et al. NIH disease funding levels and burden of disease. PLoS ONE 6, e16837 (2011). source

In the paper

“and the presence of such variation complicates identification of disease-relevant variants.”

In the paper

“An initial concern regarding GWAS meta-analysis was that increased signal from combining multiple samples would be negated by “noise” due to inter-site differences. This theoretical concern has not been borne out in practice, as illustrated above with the examples in SCZ, 58 BIP, 59 smoking behavior, 92 alcohol consumption, 100 and AD. 35,36”

In the paper

“For example, T2DM and breast cancer loci identified in European samples tend to replicate in samples of East Asian ancestry. 150,151”

What the sources say

• Not checked yetcites [150] Sullivan, P. F. The Psychiatric GWAS Consortium: big science comes to psychiatry. Neuron 68, 182–186 (2010). source
• Not checked yetcites [151] Waters, K. M. et al. Consistent association of type 2 diabetes risk variants found in Europeans in diverse racial and ethnic groups. PLoS Genet. 6, e1001078 (2010). source

In the paper

“More quantitatively, if 1% of cases are caused by fully penetrant mutations in a single gene with no background confounding variation, then observing 10 deleterious mutations in 1,000 cases and 0 in 1,000 controls would not stand out in test statistics from 20,000 genes.”

In the paper

“More realistic scenarios (including locus heterogeneity, incomplete penetrance, and background variation) will substantially erode the signal.”

In the paper

“Thus, owing to chance, a researcher would expect to find a functional exonic mutation – possibly in a gene with intriguing biology – in one case sample and none of their control samples.”