Article

Score test for detecting linkage to complex traits in selected samples

Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, University of Leiden, PO Box 9604, Leiden, The Netherlands.
Genetic Epidemiology (Impact Factor: 2.6). 09/2004; 27(2):97-108. DOI: 10.1002/gepi.20012
Source: PubMed

ABSTRACT

We present a unified approach to selection and linkage analysis of selected samples, for both quantitative and dichotomous complex traits. It is based on the score test for the variance attributable to the trait locus and applies to general pedigrees. The method is equivalent to regressing excess IBD sharing on a function of the traits. It is shown that when population parameters for the trait are known, such inversion does not entail any loss of information. For dichotomous traits, pairs of pedigree members of different phenotypic nature (e.g., affected sib pairs and discordant sib pairs) can easily be combined as well as populations with different trait prevalences.

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    ABSTRACT: Human growth and attained height are determined by a combination of genetic and environmental effects and in modern Western societies > 80% of the observed variation in height is determined by genetic factors. Height is a fundamental human trait that is associated with many socioeconomic and psychosocial factors and health measures, however little is known of the identity of the specific genes that influence height variation in the general population. This thesis work aimed to identify the genetic variants that influence height in the general population by genome-wide linkage analysis utilizing large family samples. The study focused on analysis of three separate sets of families consisting of: 1) 1,417 individuals from 277 Finnish families (FinnHeight), 2) 8,450 individuals from 3,817 families from Australia and Europe (EUHeight) and 3) 9,306 individuals from 3,302 families from the United States (USHeight). The most significant finding in this study was found in the Finnish family sample where we a locus in the chromosomal region 1p21 was linked to adult height. Several regions showed evidence for linkage in the Australian, European and US families with 8q21 and 15q25 being the most significant. The region on 1p21 was followed up with further studies and we were able to show that the collagen 11-alpha-1 gene (COL11A1) residing at this location was associated with adult height. This association was also confirmed in an independent Finnish population cohort (Health 2000) consisting of 6,542 individuals. From this population sample, we estimated that homozygous males and females for this gene variant were 1.1 and 0.6 cm taller than the respective controls. In this thesis work we identified a gene variant in the COL11A1 gene that influences human height, although this variant alone explains only 0.1% of height variation in the Finnish population. We also demonstrated in this study that special stratification strategies such as performing sex-limited analyses, focusing on dizygous twin pairs, analyzing ethnic groups within a population separately and utilizing homogenous populations such as the Finns can improve the statistical power of finding QTL significantly. Also, we concluded from the results of this study that even though genetic effects explain a great proportion of height variance, it is likely that there are tens or even hundreds of genes with small individual effects underlying the genetic architecture of height. Ihmisen kasvu ja aikuisiän pituus ovat tyypillisiä monitekijäisiä ominaisuuksia, joihin vaikuttavat sekä geneettiset tekijät että ympäristötekijät. Geneettisten tekijöiden merkitys pituuden määräytymisessä on huomattava ja on arvioitu, että kehittyneissä maissa nämä selittävät yli 80 % ihmisten välisistä pituuseroista. Aikuisiän pituudella on havaittu olevan yhteys lukuisiin sairauksiin sekä sosioekonomisiin, psykososiaalisiin ja terveydentilaa kuvaaviin muuttujiin, mutta pituuden määräytymiseen vaikuttavat geenit ovat pitkälti tuntemattomia toistaiseksi. Tässä väitöskirjatyössä pyrittiin paikantamaan pituuteen vaikuttavia kromosomialueita perimänlaajuisen kytkentäanalyysin avulla hyödyntäen poikkeuksellisen laajoja perheaineistoja. Lisäksi kytkeytyneiltä kromosomialueilta pyrittiin tunnistamaan assosiaatioanalyysin keinoin näillä alueilla sijaitsevia geenimuotoja, jotka vaikuttavat ihmisten välisiin pituuseroihin. Väitöskirjatyö koostui kolmesta osatyöstä, joissa kussakin hyödynnettiin suurta perheaineistoa: 1) FinnHeight, joka käsitti 1417 henkilöä 277 suomalaisesta perheestä, 2) EUHeight, joka sisälsi yhteensä 8450 henkilöä 3817 australialaisesta, tanskalaisesta, suomalaisesta, ruotsalaisesta ja englantilaisesta kaksosperheestä sekä 3) USHeight joka koostui yhteensä 9371 henkilöä 3032 yhdysvaltalaisesta perheestä. Tutkimuksen merkittävin tulos havaittiin ensimmäisessä osatyössä, jossa osoitettiin tilastollisesti merkitsevä kytkentä kromosomialueelle 1p21. Toisessa ja kolmannessa osatyössä puolestaan havaittiin usean kromosomialueen kytkeytyvän pituuteen, joista merkittävimmät olivat 8q21 ja 15q25. Kromosomialueen 1p21 jatkotutkimukset osoittivat alueella sijaitsevan kollageeni 11-alfa-1 (COL11A1) geenin assosioituvan pituuteen. Tämä assosiaatio toistettiin laajassa, 6542 yksilön suomalaisessa väestöaineistossa (Terveys 2000), jossa kyseisen geenimuodon suhteen samanperintäiset miehet olivat 1,1 cm ja naiset 0,6 cm pidempiä verrokkeihin nähden. Tässä tutkimuksessa paikannettiin ja tunnistettiin pituuteen vaikuttavan geenimuoto COL11A1-geenissä, joka selittää 0,1 % pituuden kokonaisvaihtelusta suomalaisväestössä. Lisäksi tutkimuksessa osoitettiin, että erityiset aineiston valikointitavat kuten sukupuolten, kaksosparien ja etnisten ryhmien erillisanalyysit voivat lisätä kytkentäanalyysin voimaa merkittävästi. Tutkimuksen merkittävin geenilöydös COL11A1-geenissä antaa myös viitteitä siitä, että vaikka suurin osa pituuden vaihtelusta on geneettisten tekijöiden määräämää, on todennäköistä, että tällaisia tekijöitä on hyvin suuri määrä ja kunkin yksittäinen geenimuodon vaikutus yksilön pituuteen on erittäin pieni.
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