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Large-scale genomics unveils the genetic architecture of psychiatric disorders

Abstract

Family study results are consistent with genetic effects making substantial contributions to risk of psychiatric disorders such as schizophrenia, yet robust identification of specific genetic variants that explain variation in population risk had been disappointing until the advent of technologies that assay the entire genome in large samples. We highlight recent progress that has led to a better understanding of the number of risk variants in the population and the interaction of allele frequency and effect size. The emerging genetic architecture implies a large number of contributing loci (that is, a high genome-wide mutational target) and suggests that genetic risk of psychiatric disorders involves the combined effects of many common variants of small effect, as well as rare and de novo variants of large effect. The capture of a substantial proportion of genetic risk facilitates new study designs to investigate the combined effects of genes and the environment.

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Figure 2: The trajectory of GWAS discoveries for SCZ and other psychiatric disorders in comparison to Crohn's disease and inflammatory bowel disease.
Figure 3: Not all GWASs are created equal under a polygenic architecture.
Figure 1: Genetic discoveries for SCZ, irrespective of risk allele frequency, variant type (SNP or CNV) or discovery method (GWAS or CNV analysis), explain approximately the same proportion of the genetic variance.
Figure 4: Paternal age at child's conception is associated with the burden of de novo mutations in the child's genome (Poisson regression, P < 2 × 10−16, linear slope = 1.75 mutations per year).
Figure 5: Quantifying the genetic relationship between independent data sets through the SNP correlation20,71,91,92.

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Acknowledgements

This work was supported by the US National Institutes of Health (GM099568 and GM075091 to P.M.V.), the National Institute of Mental Health (K01MH085812 and R01MH100141 to M.C.K.), the Australian Research Council (FT0991360 to N.R.W.) and the Australian National Health and Medical Research Council (APP1011506, APP1048853 and APP1067795 to P.M.V., APP1011506 and APP1047956 to N.R.W., APP1067795 to J.G.).

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Correspondence to Peter M Visscher.

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Glossary

Locus

A locus is a place on a chromosome. A locus may contain one gene, multiple genes or no genes at all.

Allele

An allele is one of a number of alternative forms of a gene or locus. The minor allele is the less frequent allele at a locus and the major allele is the more frequent allele.

Whole-genome sequencing (WGS)

Whole-genome sequencing (WGS) is the sequencing of all of the DNA in an individual's genome.

Exome

The exome is the part of a genome that encodes proteins, approximately 1% of the human genome.

Common variant

Common variant generally refers to an allele that segregates in a population at an allele frequency of at least 5%.

Rare-variant association study (RVAS)

A rare-variant association study (RVAS) is a genome-wide association study to discover rare variants that, as a group, present at different frequencies in affected and unaffected individuals. RVAS can be performed by whole-genome or whole-exome sequencing.

de novo mutation (DNM)

A de novo mutation (DNM) is a mutation that is part of an individual's genome that is not detected in the genome of either parent (although it may have arisen from a mutation in the parental germline). With the exception of de novo mutations in monozygotic twins, or those shared by siblings as a result of germline mosaicism, most new mutations are not shared by relatives and do not contribute to heritability estimates.

Genome-wide association study (GWAS)

A genome-wide association study (GWAS) is an unbiased screen of the genome for genetic variants that present at different frequencies in affected and unaffected individuals, that is, that associate with a phenotype. Although either rare or common variants can now be studied and analyzed for association in a genome-wide way, GWAS has historically referred to a specific, early type of genome-wide study in which a genome-wide set of common polymorphisms (single nucleotide polymorphisms) is analyzed using microarray-based technologies to find disease-associated common alleles.

Copy number variation (CNV)

A copy number variation (CNV) is a type of submicroscopic genetic variation involving the deletion or duplication of a genomic region. Although CNVs can involve genomic segments as small as a kilobase or as large as several megabases, most CNVs detected are relatively large (100 kilobases or larger) because of the resolution of genotyping arrays; in the future, sequencing-based studies may analyze many smaller CNVs.

Whole-exome sequencing (WES)

Whole-exome sequencing (WES) is the targeted enrichment and sequencing of the set of all protein-coding exons and non-coding RNAs in the genome (the exome). WES is performed by selectively capturing the protein-coding part of the genome by hybridization to pre-designed oligonucleotide 'baits'. The captured DNA is then sequenced. Although WES offers a less-complete view of an individual's genome sequence than whole-genome sequencing, WES has been more frequently used because of its substantially lower cost. As the price of sequencing continues to fall, WES may be gradually replaced by whole-genome sequencing.

Candidate gene

A candidate gene is a pre-specified gene of potential interest. Candidate gene studies are often distinguished from unbiased genome-wide studies that analyze variation in all or most genes simultaneously.

Common variant

Common variant generally refers to an allele that segregates in a population at an allele frequency of at least 5%.

Polygenic

Polygenic is a term meaning "many genes". A polygenic phenotype is influenced by more than one gene and can refer to common variants with small effects or rare variants with larger effects.

Complex disease

A complex disease describes a disorder caused by many contributing factors, both genetic and non-genetic, and does not display a simple pattern of inheritance.

Genotyping arrays

Genotyping arrays are a microarray-based technology that allows the inexpensive typing of hundreds of thousands of single-nucleotide variants (single nucleotide polymorphisms) and the ascertainment of simpler, larger forms of copy number variation. Because common variants can be systematically cataloged and assays for them placed on microarray platforms, genotyping arrays are used to perform genome-wide association studies for common variants.

Odds ratio (OR)

An odds ratio (OR) measures the effect size of a genetic variant. An OR of 1 means that the variant has no effect, OR > 1 is risk-conferring and OR < 1 is protective.

Proband

A proband is an individual being studied or reported on. The term is often used to refer to an individual affected with a disease or disorder, as distinct from their unaffected relatives.

Trio family study

A trio family study is an analysis of probands and both of their parents. Sequencing-based trio studies often focus on de novo mutations that are present in the proband's genome, but are not detected in the genomes of his or her parents.

Case-control study

A case-control study is a study design that compares the distribution of a genetic or other variable between individuals affected with a disease (cases) and unaffected individuals (controls).

Heritability

Heritability refers to the proportion of phenotypic variance of a trait, such as disease liability, that can be attributed to genetic factors.

Mutational target

Mutational target refers to the proportion of the genome, or the number of genes, that harbor causal genetic variation for a complex trait or disease.

Low-frequency variant

Low-frequency variant refers to a variant that is not common, but still segregates in a population at an appreciable frequency (for example, 0.1 to 5%) and is observed in the genomes of multiple individuals who are not closely related.

Single-nucleotide polymorphism (SNP)

A single-nucleotide polymorphism (SNP) is a single base-pair position in the genome that varies between members of a species. The terms polymorphism and SNP generally refer to sequence variations that segregate in a population at an allele frequency of at least 1%.

Mendelian disease

A Mendelian disease describes a single gene disorder that is caused by the presence of one (dominant) or two (recessive) alleles.

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Gratten, J., Wray, N., Keller, M. et al. Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17, 782–790 (2014). https://doi.org/10.1038/nn.3708

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