Glossary of Terms
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Affymetrix® Genome-Wide Human SNP Array 6.0: A microarray (sometimes called a “chip”) consisting of small DNA probes used to test an individual’s DNA for genetic variation. This array features more than 1.8 million markers for genetic variation, including more than 906,600 SNPs.
Genome wide association (GWA) study: A research study designed to discover the genetic basis of a given disease or condition. Such studies usually involve a fairly large number of subjects (i.e., ~1,000 cases and ~1,000 controls) and consist of screening the DNA of these individuals with a large number (~104 → ~106) of genetic markers (SNPs) which span the entire genome. Significant “hits” (statistically significant deviations from an expected random inheritance of SNP alleles at a given locus if there were no association between the SNP and the disease/condition) are found based on a number of statistical tests. Such associations often require replication (another independent study with the same results) in order to be accepted as a true association with a high level of confidence.
Adjusted Trend: In the context of the Gene Essence™ Report, Adjusted Trend is calculated by multiplying calculated Genetic Trend (see below) value by the percentage of the population with the lower or same value.
Allele: One of the variant forms of a gene or nucleotide sequence at a particular locus on a chromosome. With respect to SNPs associated with diseases or conditions, one allele is often referred to as the “risk” allele which means this is the variant form of the SNP most often found associated with that particular disease or condition. Association in this context means that one of the SNP alleles (the “risk” allele) is found at a higher frequency in cases when compared to controls. Since most SNPs are biallelic (a SNP which detects two variant forms) one form is designated the risk allele and the other form is designated the non-risk allele.
Buccal cells: Cells which line the inside of the cheek. When collected on a brush or swab, these cells serve as the source of DNA for the Gene Essence™ SNP test. Since all cells in the body contain identical copies of all the chromosomes (except for sperm or egg cells which contain only one of each pair of chromosomes) the buccal cells provide a readily available source of DNA for determining an individual’s genotype.
Case: In a genome wide association study, those individuals in a particular population who have been selected on the basis of having the disease (or phenotype) being studied.
Control: In a genome wide association study, those individuals in a particular population who have been selected on the basis of not showing symptoms of the disease (or phenotype) being studied.
dbSNP: The Single Nucleotide Polymorphism (SNP) database at National Center for Biotechnology Information (NCBI) is a public-domain archive for a broad collection of simple genetic polymorphisms for a variety of organisms, including human. This collection of polymorphisms includes single-base nucleotide substitutions (also known as single nucleotide polymorphisms or SNPs), small-scale multi-base deletions or insertions, called IN-DELS (also called deletion insertion polymorphisms or DIPs), and retroposable element insertions and microsatellite repeat variations (also called short tandem repeats or STRs). Each dbSNP entry includes the sequence context of the polymorphism (i.e., the surrounding sequence), the occurrence frequency of the polymorphism (by population or individual), and the experimental method(s), protocols, and conditions used to assay the variation.
Gene: A segment of DNA that enables the transfer of information from parent to offspring. A gene is the functional and physical unit of heredity. Most genes encode information for making specific proteins.
Genetic Trend: In the context of the Gene Essence™ Report, this term is used to characterize the sum of Odd Ratios of individual's risk associated genotypes, compared to the scenario in which an individual would carry the maximal genetic risk.
Genome wide association (GWA) study: A research study designed to discover the genetic basis of a given disease or condition. Such studies usually involve a fairly large number of subjects (i.e., ~1,000 cases and ~1,000 controls) and consist of screening the DNA of these individuals with a large number (~104 → ~106) of genetic markers (SNPs) which span the entire genome. Significant “hits” (statistically significant deviations from an expected random inheritance of SNP alleles at a given locus if there were no association between the SNP and the disease/condition) are found based on a number of statistical tests. Such associations often require replication (another independent study with the same results) in order to be accepted as a true association with a high level of confidence.
Genotype: In the context of the Gene Essence™ Report, this term is used to identify the specific forms of the SNPs found at each locus.
Hardy-Weinberg equilibrium: The expected distribution of alleles in a population at a given locus under random mating. If p designates the frequency of the major allele (the more common or frequent allele in the population) and q designates the frequency of the minor allele (the least common allele) then the probability of genotypes in a given population are predicted to be: PP (homozygous for the p allele) = p2, QQ (homozygous for the q allele) = q2, and PQ (heterozygote) = 2pq.
Heterozygote: Designates an individual who possesses two different forms of a particular gene or SNP, one inherited from each parent. Such an individual is said to be “heterozygous” for that gene or SNP.
Homozygote: Designates an individual who possesses two identical forms of a particular gene or SNP, one inherited from each parent. Such an individual is said to be “homozygous” for that gene or SNP.
Incidence (disease): The incidence of a disease is the rate at which new cases occur in a population during a specified period.
Locus: Refers to the position on a chromosome where a specific gene or nucleotide sequence is located.
Marker (also termed genetic marker): A segment of DNA with a known locus whose inheritance can be followed (e.g., SNPs are also called genetic markers). Markers may be “linked” to a gene, or an inherited trait on the basis of their respective DNA segments being near to each other on a chromosome. A marker (or SNP) can be a polymorphic segment of DNA with no known function, but can serve to mark the approximate location of a specific inherited disease or condition on the basis of a tight association or linkage with that disease or condition. Genes and their functional mutations responsible for a disease are often later identified after first finding markers for the trait which mark the approximate location for the gene of interest (this approach has often been termed “positional cloning”).
Multiplicative disease model: A model used in evaluation of genotype data from a genome wide association study which assumes that alleles have independent effects on disease penetrance (i.e., Homozygote OR = Heterozygote OR2).
Nucleotide: One of the building block components of DNA. There are four different types of nucleotides in DNA. A nucleotide will consist of a molecule of sugar, phosphoric acid and one of four bases: adenine (A), guanine (G), thymine (T), and cytosine (C). The four bases A, G, C, and T, are often used to identify the genotype of an individual for a specific SNP at a given locus.
Odds ratio (OR): In genetic studies looking for associations between SNPs and diseases, including GWA studies, the odds ratio (OR) is the statistic conventionally used to compare the frequency of SNP alleles between the Case and Control groups in order to determine whether a given SNP is “associated” with the disease, or not. The odds ratio is a way of comparing whether the probability of a certain event is the same for two groups. An odds ratio of 1 implies that the event is equally likely in both groups. When an odds ratio is greater than one when comparing cases to controls, it implies that, for a given SNP, one of the alleles is more likely to be found in the case group than in the controls. In many studies reported in the scientific literature, ORs are often calculated based on either the difference in allele frequencies for a given SNP between the cases and controls (allele-based single-locus test), or by observing the number of homozygotes (for each allele) and heterozygotes in the cases and controls (genotype-based single-locus test). For example, using an allele-based single-locus test and a SNP that detects alleles M and m, an OR of 1.3 would mean that allele M is 1.3 times more likely to be carried by an affected individual than allele m (assuming multiplicative disease risks and Hardy-Weinberg equilibrium at the SNP in cases and controls). For studies which report an OR for genotype MM relative to mm, an OR of 1.3 would mean that an affected individual is 1.3 times more likely to have marker genotype MM than mm. In GWA studies, a more sophisticated statistical model is often used (e.g., logistic regression) which can consider multiple SNPs, environmental factors and their interactions simultaneously. Most SNPs associated with diseases and conditions have relatively modest effects (ORs < 2) so an OR > 1 should be viewed more as an indicator of a high likelihood of a real association between the SNP and disease or condition, rather than a strict estimate of the relative risk of the disease. The odds ratio is often used as an approximation of relative risk although, strictly speaking, they are not identical.
Penetrance: How genotype dictates disease status: the percentage of individuals with a specific genotype that possess an associated phenotype. For example, some alleles are highly penetrant, meaning that nearly all individuals with such an allele will exhibit the trait of interest. Such alleles are more easily detected in genetic studies compared to alleles of reduced or low penetrance since in these cases it is difficult to distinguish genetic from environmental factors (in other words, many people will have such an allele but will not exhibit symptoms of the disease). Penetrance of a disease might also be age-related.
Phenotype: The observable traits or characteristics of an individual, for example, eye or skin color, or the presence or absence of a certain disease or condition.
Polygenic disease: Such diseases are characterized by a clear-cut hereditary component (i.e. the disease aggregates in families but without the usual Mendelian inheritance ratios for monogenic disease). The complexity of these diseases arises from the fact that a given disease may be influenced by a relatively small number or several hundred genes. Each gene might contribute an equal but small effect, or alternatively a disproportionate effect, to the susceptibility and pathology of the disease. One of the major aims of genome wide association studies is to elucidate the identity and involvement of all the genes in the molecular pathology of a polygenic disease.
Polymorphism: A common variation in DNA sequence at the same locus among individuals.
Population: In GWA studies it is critical to make sure that the cases and controls are selected from the same population (in terms of ethnic background) in order to minimize factors which could lead to false positives for a SNP – disease association. Therefore, ORs calculated for SNP – disease associations are specific to the population (ethnic background) used in the specific study and may, or may not, extrapolate to other populations.
Prevalence (disease): The prevalence of a disease is the proportion of a population that are cases at a point in time.
Risk allele: The risk allele is that form of the SNP polymorphism that has been found to be associated with a specific disease, condition or phenotype in a statistically significant manner. Individuals who have the disease or condition are more likely to carry the risk allele either as homozygotes or heterozygotes than are individuals who do not have the disease or condition. See odds ratio for the statistic conventionally used to measure the strength of the association.
rs number: An “rs number” stands for reference SNP (RefSNP). dbSNP maps each submitted SNP assay (ss) to the genome and assigns a RefSNP accession ID (rs number) to each submitted SNP assay. Submitted SNPs that map to the same location are clustered into the same RefSNP and have the same rs number. This is a way to standardize the use of SNPs and guarantees consistency across technology platforms and research studies reporting results using these polymorphisms.
Single Nucleotide Polymorphism (SNP): Variation in the nucleotide base sequence of DNA that occurs at a frequency of approximately one every 1,000 bases. SNPs are characterized based on the type of base change (e.g., A → G, C → T, A → T, etc.) and are therefore termed biallelic markers. Millions of SNPs have been catalogued in the human genome and comprise the screening technology underlying the Gene Essence™ test.
SNP/Condition Association: Associations between SNPs and various conditions including susceptibility to disease, disease states, or physical traits (like hair or eye color) are based on research studies that determine whether or not there is a correlation between one of the forms of a given SNP (an allele) and the trait being studied. Such studies involve carefully controlled comparisons between individuals exhibiting the trait and those that do not. Statistical measures are used to determine the “strength” of the association (i.e., how strong is the correlation) and therefore how useful a particular SNP may be as a “marker” for the trait being studied.
Validated SNP: A SNP which has been thoroughly tested for a specific disease association in at least one large study (~ 1,000 cases and ~ 1,000 controls), independently replicated in at least one independent study, and meets conventionally accepted scientific standards for statistical significance of association.
