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

In the paper

“One report found more rare SV in SCZ cases (odds ratio, OR=1.15), particularly for large deletions (OR=3.6). 48”

What the sources say

• Not checked yetcites [48] International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008). source

In the paper

“Finally, estimates from two different methods indicated that the risk profile component for SCZ contributes between a quarter and a third of the overall variance in liability to SCZ, 69,130 a substantial fraction of the 65–81% heritability of SCZ. 179,180”

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
• Not checked yetcites [130] Kim, Y., Zerwas, S., Trace, S. E. & Sullivan, P. F. Schizophrenia genetics: where next? Schizophr. Bull. 37, 456–463 (2011). source
• Not checked yetcites [179] Sullivan, P. F., Kendler, K. S. & Neale, M. C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003). source
• Not checked yetcites [180] Lichtenstein, P. et al. Common genetic influences for schizophrenia and bipolar disorder: a population-based study of 2 million nuclear families. Lancet 373, 234–239 (2009). source

In the paper

“De novo SV may be relevant in BIP (OR=4.8), particularly in cases with earlier ages of onset (OR=6.3). 53”

What the sources say

• Not checked yetcites [53] Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011). source

In the paper

“In SCZ, 9,394 cases and 12,462 controls were combined in a single analysis and the top 81 statistically independent loci from that analysis were then tested in over 8,000 cases. The mega-analysis identified seven significant loci (Table 3).”

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.

In the paper

“Two small exome sequencing studies 56,57 reported rates of putatively functional mutations that exceeded null expectations in SCZ cases (although the rate of de novo point mutations was not elevated in cases and specific genes were not identified).”

What the sources say

• Not checked yetcites [56] Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genet. 43, 860–863 (2011). source
• Not checked yetcites [57] Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nature Genet. 43, 864–868 (2011). source

In the paper

“For BIP, the discovery phase consisted of 7,481 cases and 9,250 controls with follow-up of 34 statistically independent loci in around 4,500 cases. Two loci exceeded genome-wide significance (Table 3).”

What the sources say

• 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

In the paper

“Large SVs are present in 5–10% of ASD cases, and the number of ASD SVs could total 130–234. 80”

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

In the paper

“There are now replicated data that vulnerability to SCZ is influenced by common genetic variation in hundreds of different loci, and this vulnerability partially overlaps that for BIP. 69”

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

“Supporting the hypothesis that this association implicates MIR137, predicted targets of miR-137 were significantly enriched for smaller GWAS p-values (p<0.01), and four of the genes that achieved genome-wide significance contain verified miR-137 binding sites. 63”

What the sources say

• Not checked yetcites [63] Bemis, L. T. et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res. 68, 1362–1368 (2008). source

In the paper

“Intriguingly, there are three instances of ASD cases with de novo deletions of 16p11.2 who also had an affected sibling without this deletion 157–159 along with similar observations for SV in 1q21.1 and 17p12. 158”

What the sources say

• Not checked yetcites [157] Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, 1999). source
• Not checked yetcites [158] Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008). source
• Not checked yetcites [159] Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007). source

In the paper

“For example, 5.8% of ASD probands had ≥1 rare de novo SV versus 1.7% of their unaffected siblings (OR=3.5), and this difference was more pronounced for SV that intersected genes. 80”

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

In the paper

“As part of the TAG consortium, 92 we determined that the components of the Fagerstrom Test for Nicotine Dependence (a measure of NIC) had heritabilities ranging from relatively high to near zero with important common environmental effects.”

What the sources say

• Not checked yetcites [92] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994).

In the paper

“Specifically, there are now multiple high-confidence SV (Table 2), rare exonic variants (currently only for ASD, AD, and ALC), and an increasing number of robustly significant and replicated common variants (Table 3).”

In the paper

“There are no known Mendelian variants, and power analyses can exclude common variants of modest effect (genotypic relative risk > 1.5 for allele frequencies > 0.1).”

In the paper

“There are multiple SVs that are rare, strong, but non-specific risk factors (Table 2), and 17 common variant associations of subtle effects (Table 3).”

In the paper

“the 10 loci identified to date account for ~20% of the total variation in risk or ~33% of the risk attributable to genetic effects, with the major contribution being from APOE”

What the sources say

• Not checked yetcites [33] Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41, 1088–1093 (2009). source
• Not checked yetcites [34] Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094–1099 (2009). source
• Not checked yetcites [35] Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429–435 (2011). source
• Not checked yetcites [36] Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genet. 43, 436–441 (2011). source

In the paper

“These advances have mostly been via genome-wide association (GWAS) and structural variation (SV) studies”

In the paper

“None is fully penetrant, and nearly all appear to be non-specific as risk is often increased for SCZ, ASD, developmental delay, mental retardation, epilepsy, somatic dysmorphism, and extremes of body mass and head size.”

In the paper

“A sign test for consistency between the mega-analysis and follow-up stage was highly significant, implying that many of the 81 top loci include true risk loci but that power was insufficient.”

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.

In the paper

“For BIP, there are reports of increased 51–53 and similar SV burden in cases versus controls 54,55”

What the sources say

• Not checked yetcites [51] Zhang, D. et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol. Psychiatry 14, 376–380 (2009). source
• Not checked yetcites [52] Priebe, L. et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol. Psychiatry 17, 421–432 (2011). source
• Not checked yetcites [53] Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011). source
• Not checked yetcites [54] Grozeva, D. et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch. Gen. Psychiatry 67, 318–327 (2010). source
• Not checked yetcites [55] McQuillin, A. et al. Analysis of genetic deletions and duplications in the University College London bipolar disorder case control sample. Eur. J. Hum. Genet. 19, 588–592 (2011). source

In the paper

“This implies that sample sizes are insufficient and that additional loci can be discovered in larger samples.”

In the paper

“This suggests the discovery sample was insufficiently large to identify many true risk loci at even nominal levels of significance: adding more SNPs contributed more genetic signal than noise.”

In the paper

“Remarkably, the same set of markers also discriminated BIP cases from controls indicating substantial genetic contributions between SCZ and BIP.”

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

“The evidence for association is compelling but high gene density and exceptionally high linkage disequilibrium complicate the identification of specific sequence variation.”

In the paper

“Indeed, ASD mutations with very high penetrance are exceptional (i.e., Rett syndrome mutations in MECP2 and CDKL5), and Mendelian diseases enriched for ASD have far less than complete penetrance (e.g., Fragile X syndrome and tuberous sclerosis). 78”

What the sources say

• 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

“In addition, ASD has been noted as a comorbid feature of >100 single gene, Mendelian medical genetic syndromes, 79 although the penetrance and confidence of the clinical associations are variable.”

What the sources say

• Not checked yetcites [79] Folstein, S. E. & Rosen-Sheidley, B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nature Rev. Genet. 2, 943–955 (2001). source

In the paper

“Further, results from SGENE+ 60 implicate NRGN (neurogranin) which may act as a calcium sensor. 61”

What the sources say

• Not checked yetcites [60] Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genet. 43, 977–983 (2011). These two papers are the largest and most comprehensive GWAS mega-analyses conducted for psychotic disorders. source
• Not checked yetcites [61] Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009). source

In the paper

“Similarly, a sign test between the discovery and follow-up results was highly significant, again suggesting insufficient power. 59”

What the sources say

• 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

In the paper

“miR-137 is a key regulator of neuronal development with roles in neurogenesis and maturation 64,65 and is highly expressed at synapses in the cortex and hippocampus. 66”

What the sources say

• Not checked yetcites [64] Kwon, E., Wang, W. & Tsai, L. H. Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. Mol. Psychiatry 20 Dec 2011 (doi:10.1038/mp.2011.170). source
• Not checked yetcites [65] Szulwach, K. E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010). source
• Not checked yetcites [66] Smrt, R. D. et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28, 1060–1070 (2010). source

In the paper

“Case-control studies are simpler, and most biases can be surmounted by careful study procedures, but cannot delineate rare inherited from de novo variation.”

In the paper

“Intriguingly, all three studies noted an increased rate of de novo exonic mutations in older parents (with the mutations generally being of paternal origin), 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

“A focus on multiplex pedigrees has led to the identification of specific mutations underlying hundreds of Mendelian disorders (including ASD and AD).”

In the paper

“The 16p11.2 SV associated with ASD and SCZ has been termed a “mirror image” SV since the deletion and duplication are associated with increased and reduced head and body size.”

In the paper

“However, it is difficult to understand the clinical features of ASD and SCZ as mirror images and, more importantly, ASD is associated with both 16p11.2 deletions and duplications.”

In the paper

“Simplex-based ascertainment is tailored to evaluate de novo mutations, and predicated on a model in which disorder with dramatically reduced fecundity and a proven role of de novo SV might be explicable as a series of Mendelian disorders attributable to recent high-penetrance mutations in any of a large number of genes.”

In the paper

“It has also been pointed out that de novo events must confer risk in multiplex families, as such mutations increase the chance that an individual is affected and increase risk in that person’s offspring.”

In the paper

“For ALC, the published GWAS are small and no large-scale meta-analysis has been conducted. 93–97”

What the sources say

• Not checked yetcites [93] Tobacco and Genetics Consortium. Meta-analyses of genome-wide association studies implicate multiple loci for smoking behavior. Nature Genet. 42, 441–447 (2010). source
• Not checked yetcites [94] Edenberg, H. J. et al. Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol. Clin. Exp. Res. 34, 840–852 (2010). source
• Not checked yetcites [95] Bierut, L. J. et al. A genome-wide association study of alcohol dependence. Proc. Natl Acad. Sci. USA 107, 5082–5087 (2010). source
• Not checked yetcites [96] Kendler, K. S. et al. Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcohol. Clin. Exp. Res. 35, 963–975 (2011). source
• 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

“Additional support for our recommendation for more GWAS is provided by Voineagu et al. who identified a gene expression module that had attenuated expression in post-mortem brain samples of individuals with ASD and which also had enrichment for GWAS 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

“Associations to this region have also bee reported for lung cancer. 105,106”

What the sources say

• Not checked yetcites [105] Saccone, N. L. et al. Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet. 6, e1001053 (2010). source
• Not checked yetcites [106] Thorgeirsson, T. E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008). source

In the paper

“A provocative finding from 2003 was that risk for MDD might be influenced by a gene-environment interaction with genetic variation near the serotonin transporter. 110”

What the sources say

• Not checked yetcites [110] Rucker, J. J. et al. Genome-wide association analysis of copy number variation in recurrent depressive disorder. Mol. Psychiatry 1 Nov 2011 (doi:10.1038/mp.2011.144). source

In the paper

“These null results are intriguing as almost all other published GWAS with N>11,000 for any disease has found at least one genome-wide significant finding.”

In the paper

“The most likely reasons for these results are particularly high heterogeneity of MDD and insufficient power arising from its lower heritability. 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

“There is an important component arising from common variation in hundreds of different loci (Box 3), and larger sample sizes are likely to convert many of these to genome-wide significance.”

In the paper

“The data support multiple novel biological hypotheses (for example, cholesterol metabolism and the innate immune response in AD, a network involving miR-137 for SCZ, calcium signaling for BIP and SCZ, and chromatin remodeling for ASD) and reinforce previous hypotheses such as synaptic biology for SCZ and ASD).”

In the paper

“For disorders with sufficient data (AD, BIP, and SCZ), the results are consistent with an allelic spectrum and an etiological role for both rare and common variation.”

In the paper

“Although we were initially agnostic 123 we now believe that the data support both positions.”

In the paper

“Common variant SNP effects have been estimated to explain large proportions of the phenotypic heritability for a wide range of diseases: BIP and SCZ; 69,130 T1DM, T2DM, Crohn’s disease, rheumatoid arthritis, celiac disease, and coronary artery disease; 70,77 and continuous traits (height, intelligence, and body mass). 70,131,132”

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
• Not checked yetcites [130] Kim, Y., Zerwas, S., Trace, S. E. & Sullivan, P. F. Schizophrenia genetics: where next? Schizophr. Bull. 37, 456–463 (2011). source
• 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 [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 [131] Lee, S. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genet. 44, 247–250 (2012). This is a provocative paper showing that liability to SCZ is substantial and distributed among genetic variants across the common variant spectrum and across the genome. The authors suggest that the so-called missing heritability problem is hidden and that the architecture of SCZ is polygenic. source
• 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

“There are statistical hints that ADHD and MDD might also be polygenic.”

In the paper

“the knowledge base in psychiatric genetics is vastly greater than five years ago, and the rate of change is unprecedented in the history of the field.”

In the paper

“For example, SV testing is often part of the clinical evaluation of ASD”

In the paper

“It is possible to provide realistic estimates of power and to predict the number of new associations for each increment in sample size 128,129,140”

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
• Not checked yetcites [140] Miller, G. Is pharma running out of brainy ideas? Science 329, 502–504 (2010). source

In the paper

“The genomic search space is large but finite and so, in theory, elucidating the parts list for a psychiatric disorder could be achieved.”

In the paper

“A comprehensive portrait of genetic architecture does not now exist for any psychiatric disorder.”

In the paper

“there have been multiple meta-analysis 146,147 consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium (http://pgc.unc.edu) is the largest and most encompassing. 123,148,149”

What the sources say

• Not checked yetcites [123] McClellan, J. & King, M. C. Genomic analysis of mental illness: a changing landscape. JAMA 303, 2523–2524 (2010). source
• Not checked yetcites [148] de Bakker, P. I., Neale, B. M. & Daly, M. J. Meta-analysis of genome-wide association studies. Cold Spring Harb. Protoc. 2010, pdb.top81 (2010). source
• Not checked yetcites [149] Psychiatric GWAS Consortium. Genome-wide association studies: history, rationale, and prospects for psychiatric disorders. Am. J. Psychiatry 166, 540–546 (2009). source

In the paper

“For example, the lifetime cost per person with SCZ is on the order of $US 1.4 million: 145”

What the sources say

• Not checked yetcites [145] Lamarre-Cliche, M., Castilloux, A. M. & LeLorier, J. Association between the burden of disease and research funding by the Medical Research Council of Canada and the National Institutes of Health. A cross-sectional study. Clin. Invest. Med. 24, 83–89 (2001).

In the paper

“The successful study of any type of genetic variation in complex biomedical diseases requires very large sample sizes as a means to cut the Gordian knot posed by genetic architecture, etiological complexity, and phenotypic uncertainty.”

In the paper

“Genomic technologies routinely posit 105–108 hypotheses, and false positives are a serious concern.”

In the paper

“Humans carry a huge pool of phenotypically-neutral background variation that adds noise to genetic analyses (for example, each person has ~100 loss-of-function variants, most of which are rare in a population), 152,153”

What the sources say

• Not checked yetcites [152] Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007). source
• Not checked yetcites [153] MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012). source

In the paper

“Indeed, a GWAS co-authorship network graph demonstrates the high connectedness of researchers in the field (Figure S2).”

In the paper

“The published results for ASD 83–85 and unpublished data on SCZ suggest these issues will be important and underscore the need for sequencing studies to have the same emphasis on statistical rigor and large sample sizes that has enabled GWAS to realize success for multiple psychiatric disorders. 154”

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
• Not checked yetcites [154] Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010). source

In the paper

“the genetics knowledge base has advanced considerably during the past five years, and results to date contain clear indications that further study will yield greater insight.”