Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2

Abstract

Late-onset familial Alzheimer disease (LOFAD) is a genetically heterogeneous and complex disease for which only one locus, APOE, has been definitively identified. Difficulties in identifying additional loci are likely to stem from inadequate linkage analysis methods. Nonparametric methods suffer from low power because of limited use of the data, and traditional parametric methods suffer from limitations in the complexity of the genetic model that can be feasibly used in analysis. Alternative methods that have recently been developed include Bayesian Markov chain-Monte Carlo methods. These methods allow multipoint linkage analysis under oligogenic trait models in pedigrees of arbitrary size; at the same time, they allow for inclusion of covariates in the analysis. We applied this approach to an analysis of LOFAD on five chromosomes with previous reports of linkage. We identified strong evidence of a second LOFAD gene on chromosome 19p13.2, which is distinct from APOE on 19q. We also obtained weak evidence of linkage to chromosome 10 at the same location as a previous report of linkage but found no evidence for linkage of LOFAD age-at-onset loci to chromosomes 9, 12, or 21.

Figure 1

MCMC multipoint linkage analysis of chromosome 19, expressed as the IR, with a prior variance on QTL genotype effects of τ_β=100. The solid line indicates results obtained with the 12 markers in the marker screening panel. The dashed line denotes results obtained when APOE was added as a 13th marker. The heavy dotted line shows results when APOE was added as both a 13th marker and a covariate. The vertical light dotted line marks the location of APOE, and the horizontal light dotted line represents IR=1. Marker locations are indicated by tick marks on the top horizontal axis. Markers, from left (19p) to right (19q), are D19S209, D19S216, D19S884, D19S221, D19S226, D19S414, D19S220, D19S420, D19S902, D19S571, D19S418, and D19S210.

Figure 2

MCMC multipoint linkage analysis, with 21 markers plus APOE, which was used as both a marker and a major-gene covariate. The solid line indicates τ_β=100, and the dashed line represents τ_β=200. The vertical light dotted line shows the location of APOE. APOE genotypes were inferred probabilistically for all individuals with missing genotypes, and age at onset was estimated for all six APOE genotypes. Tick marks on the top horizontal axis indicate marker locations, with long ticks corresponding to the same markers as in figure 1 and short ticks corresponding to an additional nine markers. From left to right, the markers are D19S209, D19S894, D19S216, D19S869, D19S395, D19S884, D19S391, D19S916, D19S394, D19S221, D19S914, D19S564, D19S226, D19S915, D19S414, D19S220, D19S420, D19S902, D19S571, D19S418, and D19S210. (Markers D19S221 and D19S914 are so close together that the ticks are indistinguishable.)

Figure 3

Results from run with τ_β=100 in figure 2, showing position and genetic effect of the 19p linkage signal relative to the background signal. The vertical axis is proportional to the posterior probability of a gene at a particular location (the intensity) and with the indicated QTL size (square root of the genetic variance).

Figure 4

LOP score distribution for chromosome 19 (τ_β=100; 2,500,000 scored iterations), showing position and genetic effect of the 19p linkage signal relative to the background signal. The vertical axis is on a log₁₀ scale.

Figure 5

MCMC multipoint linkage analysis results for chromosomes 9, 10, 12, and 21. Tick marks on the top horizontal axis represent marker locations. Chromosome 9 markers: D9S288, D9S286, D9S285, D9S157, D9S171, D9S161, D9S1817, D9S273, D9S175, D9S167, D9S23, D9S287, D9S1690, D9S1677, D9S1776, D9S1682, D9S290, D9S164, D9S1826, D9S158. Markers on chromosome 10: D10S249, D10S591, D10S189, D10S547, D10S1653, D10S548, D10S197, D10S208, D10S196, D10S1652, D10S537, D10S1686, D10S185, D10S192, D10S597, D10S1693, D10S587, D10S217, D10S1651, and D10S212. Chromosome 12 markers: D12S352, D12S99, D12S336, D12S364, D12S310, D12S1617, D12S1042, D12S345, D12S1090, D12S85, D12S368, D12S390, D12S83, D12S326, D12S351, D12S346, D12S78, D12S79, D12S86, D12S324, D12S1659, and D12S1723. Chromosome 21 markers: D21S1911 (0 cM), D21S1904, D21S1899, D21S1884, D21S1922, D21S214, D21S1914, D21S269, D21S263, D21S1252, D21S1255, and D21S266. Vertical lines indicate the locations of previously reported linkage signals.