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Genome-scale neurogenetics: methodology and meaning


Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology.

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Figure 1: Allele frequency represents a continuum in human populations, with cutoffs between 'common' and 'rare' being somewhat arbitrary.


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The authors are supported by the Stanley Medical Research Institute.

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Correspondence to Steven A McCarroll or Steven E Hyman.

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Competing interests

S.E.H. is a consultant for AstraZeneca on early-stage drug discovery and is principal investigator of a collaboration with Novartis.


Mendelian disease

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


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


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.


Pleiotropy is the phenomenon whereby a genetic variant influences variation in more than one trait or disease.


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.

Rare variant

Rare variant describes variants that are private to individuals and families. In some usage, the term rare variant is used more expansively to include all variants that are not common.


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

Common variant

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

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.

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%.


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

Common-variant association study (CVAS)

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.

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.

Whole-genome sequencing (WGS)

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

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.

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).


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.

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.

Genetic background

Genetic background refers to the genotype of all genes that may modify the expression or presentation of a phenotype related to a gene of interest.


A haplotype is an arrangement of alleles along a chromosome. In population-based studies, a haplotype refers more specifically to a set of genomically nearby alleles that segregate in populations as a block or unit, as their physical linkage is seldom, if ever, disrupted by recombination.

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.

Linkage disequilibrium (LD)

Linkage disequilibrium (LD) refers to the tendency of genomically nearby alleles to segregate as haplotypes or in other non-random patterns, as a result of their inheritance from shared, common ancestors, and the sparse and hotspot-concentrated distribution of recombination events in human ancestors, which allows LD relationships to persist across thousands of generations, usually at spatial scales in the tens of kilobases.

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.

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McCarroll, S., Feng, G. & Hyman, S. Genome-scale neurogenetics: methodology and meaning. Nat Neurosci 17, 756–763 (2014).

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