A Common Theme Running Through Recent Research in Genetic Epidemiology Is the Need to Find

Bacanu, et al., MS# 200200612

Linkage Analysis of Alzheimer Disease With Psychosis

Supplementary Material for Web Publishing Only

Linkage Analysis Of Alzheimer Disease With Psychosis

Late-onset Alzheimer disease (LOAD) has deep genetic roots (Bernie, I’m not sure what you mean by this. Is there a better way to say it). While a portion of risk to Late-Onset Alzheimer Disease (LOAD) is attributable to Apolipoprotein-E (Apo-E), the search for other loci is ongoing. Psychotic symptoms with LOAD (LOAD+P) identify a severe and, potentially, more etiologically homogeneous form of this diseaseAD. Linkage analysis of LOAD+P families bolsters theis conjecture of greater etiological homogeneity.

In the search for the genetic basis of Alzheimer diseaseAD, one proven strategy has been to define subphenotypes with more homogeneous genetic origins. GroupSeparatingon families byby early and late age-of-onsetage-of-onset has uncovered has led to the discovery of mutations causing early-onset 1 AD(1)11, and to revealed thethe impact significance of Apo-E ε4 alleles on for LOAD liability 122.. But Apo-E alleles are neither necessary nor sufficient to cause LOAD, so investigators have searched for other loci and other additional subphenotypes to find those loci3ci3.2

We previously hypothesizedproposed that the manifestation of psychotic symptoms with LOAD could define such a critical partition of LOADsubphenotype3(4). 44. Here we explore this possibility using linkage analysis.

Psychotic symptoms, such as hallucinations and delusions, have a cumulative incidence of 51% among patients with LOAD, and identify a more rapidly progressive phenotype: more severe cognitive deficits, faster cognitive and functional deterioration, aggressive behavior, and premature institutionalization3 Analysis55. AIndeed By analysiszing data from o ofthe National Institute of Mental Health (NIMH) Alzheimer DiseaseAD Genetics Initiative4 6ve6 data reveals, familial aggregation of LOAD+P3 5we recently demonstrated familial aggregation of LOAD+P5. For broad and narrow diagnostic categories, tIn fact, the odds ratio offor LOAD+P among siblings of LOAD+P probands, versus

siblings of in comparison to siblings of LOAD-P probands, without psychosis awerewas 2.4 and 3.2, respectively for broad and narrow diagnostic categories. In light of the siblings of LOAD probands without psychosis were 2.4 and 3.2, respectively. In light of the evidence, it seemsed reasonable to ask if linkage analysis of a LOAD+P familiesly sample might yield new signals not evident from other LOAD genome scans.

By using samples from A previous study of the data from the NIMH AD Genetics Initiative and genotyping performed genome-wide linkage analysis using short tandem repeats (STRs) at average intervals of 16.3 cM7,. This ‘Kehoe et al4.77 ’ pperformed a genome-wide linkage aanalysis of LOAD. Only individuals from families who had two or more siblings with probable or definite LOAD were genotyped. Their analyses study revealed some suggestive 8 linkage signals, many produced after accounting for the effect of ApoE on liability identifiable genetic variance by conditioning on the presence or absence of ε4 alleles, the only known risk factor, in affected siblings. Only individuals from families who had two or more siblings with probable or definite LOAD were genotyped. presence of ε4 alleles. (LOAD+ε4).

4. (1999) (Overall and Gorham 1962)8. 5 .3.5 in press).

(Blacker et al. 1997). 6. 4 (1999)7,7 (9 mm {(Kong and Cox 1997; Teng and Siegmund 19984106)} (Kruglyak et al. 1996).10

. (Teng and Siegmund 1998; Lui et al. 2001).(Terwilliger and Ott 1993)11.9 11(1995): 10Drawing on the same data, we report the first genome scan using families with two or more LOAD+ε4 siblings who were also psychotic (LOAD+P+ε4)affected by LOAD+P. PIndividuals’ psychotic symptoms were characterized during initial and follow-upclinical evaluations, and. i Individuals were classified as LOAD+P if they demonstrated more than one psychotic symptom or recurrent psychotic symptoms. Sixty-five LOAD+P families were identified, 42 of whomich had two or more individuals who were LOAD+P+ε4 had two or more individuals with ε4 alleles (LOAD+P+ε4) (Table 1). Linkage analyses of the LOAD phenotype were implemented by using GeneHunterPlus9,10 and the . For STR allele frequencies and genetic map produced by , we used those estimated by the Kehoe et alstudy7. To evaluate the results, we performed simulations11 to determine the distribution of test statistics when no disease loci were present. From 10,000 data sets for all 23 chromosomes, thresholds for significant and suggestive8 MLS scores were 3.18 and 1.70 respectively.

For our principal analysis, namely LOAD+P+ε4 families (Fig. 1), we find one significant and two suggestive linkages. The significant finding, MLS = 3.52, falls on Chromosome 2p, near marker D2S1356 (64.3 cM according to the Marshfield map; see the Marshfield web site). The suggestive linkages fall on Chromosome 6, near marker D6S1021 (112.2 cM, MLS = 2.01), and 21, at marker D21S1440 (36.8 cM; MLS = 1.94). For the total LOAD+P sample, one suggestive linkage (MLS = 2.51) occurs (Fig. 1).

W13 12(13)1112. 14.13 (15)15 13(16)14 . .{levinson} 15 16,17hile other studies have found evidence for linkage on 21q4,187,14157,12, their evidence comes from the ε4 negative families, whereas ours derives from LOAD+P+ε4 families. (We note the 21q result may not be robust because of discrepancies among maps of this region.) 1917,20,2122 (17) (1997)15 The suggestive linkage on 6q for the LOAD+P+ε4and total LOAD+P samples is more distal from the weaker linkage signal produced by the previous analysis7.

The significant linkage signal on Chromosome 2p, produced by analysis of LOAD+P+ ε4 families, has no equivalent finding in the Alzheimer disease literature. Interestingly, some support for the region can be garnered from the schizophrenia literature. Coon et al.13 reported a suggestive linkage signal in this region in a set of extended Palauan families; follow-up multipoint studies have continued to support these results14. Likewise, DeLisi et al.15 found highly suggestive linkage in the same region in a large sample of families of European ancestry. This concurrence of findings in schizophrenia and LOAD+P, however, should be interpreted cautiously. Despite the common psychosis phenotype, there are substantial clinical and neurobiological differences between the two disorders, and the chromosomal region in which linkage has been detected in these two conditions is broad.

Biologically, LOAD+P marks a more severe and rapidly progressive form of LOAD. We previously have hypothesized that LOAD+P, which marks a more severe and progressive form of LOAD, could define a more homogeneous form of LOAD for genetic study 1744. Our previous results 5 on the familiality of LOAD+P support this proposal163. While not definitive, the significant and suggestive linkages reported here bolster the case. Together they suggest that the characterization of psychosis in LOAD could open a new avenue for productive exploration of the genetic basis of LOAD.

Note: Supplementary information is available on the Nature Genetics web site (genetics.nature.com/supplementary_info/).

Acknowledgements

Supported in Part by grants AG05133 from the National Institute of Aging and MH01489, MH53459, and MH57881 from the National Institute of Mental Health. Data and biomaterials were collected in three projects that participated in the National Institute of Mental Health (NIMH) Alzheimer Disease Genetics Initiative. From 1991-98, the Principal Investigators and Co-Investigators were: Massachusetts General Hospital, Boston, MA, U01 MH46281, Marilyn S. Albert, Ph.D., and Deborah Blacker, M.D., Sc.D.; Johns Hopkins University, Baltimore, MD, U01 MH46290, Susan S. Bassett, Ph.D., Gary A. Chase, Ph.D., and Marshal F. Folstein, M.D.; University of Alabama, Birmingham, AL, U01 MH46373, Rodney C.P. Go, Ph.D., and Lindy E. Harrell, M.D.

Silviu-Alin Bacanu1, B. Devlin1, K.V. Chowdari1, Steven T. DeKosky1,2, Vishwajit L. Nimgaonkar1, and Robert A. Sweet1

Department of 1Psychiatry and 2Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213. Address correspondence to R.A.S. ().

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