View source for Haplotype-relative-risk


The '''haplotype-relative-risk''' ('''HRR''') method is a family-based method for determining gene [[allele]] [[genetic association|association]] to a disease in the presence of actual [[genetic linkage]]. [[nuclear family|Nuclear families]] with one affected child are sampled using the parental [[haplotype]]s not transmitted as a control.  While similar to the [[genotype]] [[relative risk]] (RR), the HRR provides a solution to the problem of [[population stratification]] by only sampling within family trios. The HRR method was first proposed by Rubinstein in 1981 then detailed in 1987 by Rubinstein and Falk<ref>Falk CT, Rubinstein P (1987) "Haplotype relative risks: and easy reliable way to construct a proper control sample for risk calculations". Ann Hum Genet 51:227-233</ref> and is an important tool in [[genetic association]] studies.

The original method proposed by Falk and Rubinstien fell under scrutiny in 1989, when Ott showed the equivalence of HRR to the classical RR method<ref>Woolf B (1955) "On estimating the relation between blood group and disease". Ann Human Genet 19:251-253</ref> demonstrating that the HRR holds only when there is zero chance of [[Genetic recombination|recombination]] between a disease [[Locus (genetics)|locus]] and its markers.<ref>Ott J (1989) statistical properties of the haplotype relative risk. Genetic Epidemiol 6:127-130</ref> Yet, even when the recombination factor for a locus and its genetic markers is >0 HRR estimates are still more conservative than RR estimates.<ref>Knapp, Seuchter, Baur (1987) "The haplotype-relative-risk" (HRR) method for analysis of association in nuclear families. Am J Hum Genet 52:1085-10093,1993</ref>

While the HRR method has proven an effective means of avoiding population stratification biases, another family-based association test known as the [[transmission disequilibrium test]],<ref>a b c Spielman RS, McGinnis RE, Ewens WJ (Mar 1993). "Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM)". Am J Hum Genet. 52 (3): 506–16. {{PMID|8447318}}.</ref> or TDT, is more commonly used. Some research uses both HRR and TDT for their ability to complement each other since one result may give no association while the other will. A positive association result from both TDT and HRR means there is strong evidence that a link exists and vice versa. For example, both HRR and TDT methods were used in a study looking for polymorphism in D2 and D3 [[dopamine receptor]] in association with [[schizophrenia]] and neither found any evidence for linkage,<ref>Ambròsio, Kennedy, Macciardi, macoedo, Valente, Dourado, oliveria, Carlos, Pato (2004)"Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a portuguese population". Psychiatry Research 125:185-191</ref> making an actual role of those genes in the etiology of the mental disorder all the more unlikely.

== Calculation ==

This model represents a case which there is a single locus where all genotypes may lead to expression of the allele in its most simplified definition. Under these parameters a [[linkage disequilibrium]] of more than 50% means there is a possible link to the gene allele and inheritance.

<math> HRR = \frac{P_1}{1-P_1} * \frac{1-P_2}{P_2}</math>

Gives the HHR which can be estimated by

<math> HRR = \frac{a^'}{b^'} * \frac{d^'}{c^'}</math>

a<sup>'</sup> denotes the observed frequency of children who are positive for the gene allele H.

b<sup>'</sup> denotes the observed frequency of children who are negative for the gene allele H.

c<sup>'</sup> is the observed frequency of families with at least one transmitted parental marker allele H.

d<sup>'</sup> is the observed frequency of families with no transmitted parental marker allele H.

P<sub>1</sub> is the probability this child is positive for the allele of interest H.

P<sub>2</sub> is the probability that at least one of the nontransmitted parental marker alleles equals the allele of interest H.

H is the allele of interest.<ref>Knapp, Seuchter, Baur (1987) "The haplotype-relative-risk (HRR) method for analysis of association in nuclear families". Am J Hum Genet 52:1085-10093,1993</ref>

== References==
<references/>

{{DEFAULTSORT:Haplotype-Relative-Risk}}
[[Category:Genetics]]