Recent human genetic studies have consistently shown that mutations in the same gene or same genomic region can increase the risk of a broad range of complex neuropsychiatric disorders. Despite the steadily increasing number of examples of such nonspecific effects on risk, the underlying biological causes remain mysterious. Here we investigate the phenomenon of such nonspecific risk by identifying Mendelian disease genes that are associated with multiple diseases and explore what is known about the underlying mechanisms in these more 'simple' examples. Our analyses make clear that there are a variety of mechanisms at work, emphasizing how challenging it will be to elucidate the causes of nonspecific risk in complex disease. Ultimately, we conclude that functional approaches will be critical for explaining the causes of nonspecific risk factors discovered by human genetic studies of neuropsychiatric disorders.
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The authors declare no competing financial interests.
Examples of genes associated with more than one Mendelian disease with literature supporting a relevant mechanism (XLSX 12 kb)
Schizophrenia ascertained “hot zone” de novo mutations from four schizophrenia trio sequencing studies (ref. 31, 48, 85, 89). The “hot zone” being defined as residual variation intolerance score (RVIS) ≤ 25% and variant-level PolyPhen-2 quantitative score2 ≥ 0.95 (ref. 86). (XLSX 28 kb)
- 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.
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.
- 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%.
- Copy number variation (CNV)
A common-variant association study (CVAS) is a genome-wide association study to find common variants that present at different allele frequencies in affected and unaffected individuals. The term CVAS has recently been proposed as a replacement for the term GWAS, as rare-variant association studies are also association studies and are also genome wide.
The exome is the part of a genome that encodes proteins, approximately 1% of the human genome.
- 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.
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.
- 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.
Pleiotropy is the phenomenon whereby a genetic variant influences variation in more than one trait or disease.
A locus is a place on a chromosome. A locus may contain one gene, multiple genes or no genes at all.
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.
- Next generation sequencing (NGS)
Next generation sequencing (NGS) refers to a set of technologies that sequence DNA in massively parallel ways; for example, by optically detecting the incorporation of specific bases into millions of different DNA molecules, spatially segregated on an imageable glass surface, at the same time.
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Zhu, X., Need, A., Petrovski, S. et al. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat Neurosci 17, 773–781 (2014). https://doi.org/10.1038/nn.3713
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