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Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.

Artikel i vetenskaplig tidskrift
Författare Chandra A Reynolds
Mun-Gwan Hong
Ulrika K Eriksson
Kaj Blennow
Fredrik Wiklund
Boo Johansson
Bo Malmberg
Stig Berg
Andrey Alexeyenko
Henrik Grönberg
Margaret Gatz
Nancy L Pedersen
Jonathan A Prince
Publicerad i Human molecular genetics
Volym 19
Nummer/häfte 10
Sidor 2068-2078
ISSN 1460-2083
Publiceringsår 2010
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Psykologiska institutionen
Sidor 2068-2078
Språk en
Länkar dx.doi.org/10.1093/hmg/ddq079
Ämneskategorier Psykiatri

Sammanfattning

We conducted dense linkage disequilibrium mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases (including 1270 with Alzheimer disease) and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at p approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at p approximately 10(-8)). In the present study we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best p=3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2, and GCKR). The associated markers near SREBF1 reside in a large linkage disequilibrium block, extending more than 400kb across 7 candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2)>0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

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