Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families

Abstract

We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL.

Figure 1

Highest two-point LOD scores in stage 1, for the sample group with low HDL-C, on each chromosome, as determined by use of either a recessive mode of inheritance or an ASP analysis. A dominant mode of inheritance yielded LOD scores that were typically slightly lower. The MLINK program of the LINKAGE package (Lathrop et al. 1984), version FASTLINK 4.1P (Cottingham et al. ; Schäffer et al. 1994), was used to perform the parametric linkage analyses. The parametric linkage analyses were performed with a dominant and recessive mode of inheritance by use of an affecteds-only strategy. Gene frequencies (reflecting an estimated population prevalence of ∼1%) of 0.4% and 8% were used for the dominant and recessive mode of inheritance. For each marker, the allele frequencies were estimated from all individuals, by use of the DOWNFREQ program (Göring and Terwilliger 2000b). The ASP analysis was performed using the SIBPAIR program (Kuokkanen et al. 1996) of the ANALYZE package (Göring and Terwilliger 2000a). The two-point analyses were performed using the AUTOSCAN program, a helper program that enables a genomewide scan by a single computer analysis. Multipoint analyses were performed with the Simwalk program, version 2.80 (Sobel and Lange 1996). The Mendelian errors were checked with the PedCheck program (O'Connell and Weeks 1998). The observed inconsistencies were handled by rereading raw gel data; if errors still remained, the genotypes of the particular subjects involved were coded as zeros. On chromosomes 1 and 9, two separate regions produced LOD scores >1.0 and are indicated as 1a and 1b and 9a and 9b, respectively. The recombination fraction shown is that of the two-point maximum LOD score in the parametric linkage analysis. The position given is the distance (in cM) from pter, for each marker.

Figure 2

Highest two-point LOD scores in stage 2, for the three sample groups, on each chromosome. Gray columns show the two-point results for the sample group with low HDL-C, white columns show the results for the sample group with FCHL, and black columns show the results for the pooled sample group. The chromosome numbers are given below the X-axis. The boxes indicate the chromosomes on which the identified loci were supported by the pooled data analyses. On chromosome 2, two separate regions produced LOD scores >2.0 and are indicated as 2ptel and 2p. The complete linkage results for stage 2 are available from our Web site (UCLA Human Genetics). The markers that produced the highest LOD scores separately for each sample group are given below each chromosome. The recombination fraction and position are as explained in the legend for figure 1.