Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity.
Deviations from normal body weight are observed prior to and after the onset of Alzheimer's disease (AD). Midlife obesity confers increased AD risk in later life, whereas late-life obesity is associated with decreased AD risk. The role of underweight and weight loss for AD risk is controversial. Based on the hypothesis of shared genetic variants for both obesity and AD, we analyzed the variants identified for AD or obesity from genome-wide association meta-analyses of the GERAD (AD, cases = 6,688, controls = 13,685) and GIANT (body mass index [BMI] as measure of obesity, n = 123,865) consortia. Our cross-disorder analysis of genome-wide significant 39 obesity SNPs and 23 AD SNPs in these two large data sets revealed that: (1) The AD SNP rs10838725 (pAD  = 1.1 × 10(-08)) at the locus CELF1 is also genome-wide significant for obesity (pBMI  = 7.35 × 10(-09) ). (2) Four additional AD risk SNPs were nominally associated with obesity (rs17125944 at FERMT2, pBMI  = 4.03 × 10(-05), pBMI corr  = 2.50 × 10(-03) ; rs3851179 at PICALM; pBMI  = 0.002, rs2075650 at TOMM40/APOE, pBMI  = 0.024, rs3865444 at CD33, pBMI  = 0.024). (3) SNPs at two of the obesity risk loci (rs4836133 downstream of ZNF608; pAD  = 0.002 and at rs713586 downstream of RBJ/DNAJC27; pAD  = 0.018) were nominally associated with AD risk. Additionally, among the SNPs used for confirmation in both studies the AD risk allele of rs1858973, with an AD association just below genome-wide significance (pAD  = 7.20 × 10(-07)), was also associated with obesity (SNP at IQCK/GPRC5B; pBMI  = 5.21 × 10(-06) ; pcorr  = 3.24 × 10(-04)). Our first GWAS based cross-disorder analysis for AD and obesity suggests that rs10838725 at the locus CELF1 might be relevant for both disorders.
Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, Universitätsklinikum Essen, University of Duisburg-Essen, Essen, Germany.
Anke
A
Hinney
Ozgür
O
Albayrak
Jochen
J
Antel
Anna-Lena
AL
Volckmar
Rebecca
R
Sims
Jade
J
Chapman
Denise
D
Harold
Amy
A
Gerrish
Iris M
IM
Heid
Thomas W
TW
Winkler
André
A
Scherag
Jens
J
Wiltfang
Julie
J
Williams
Johannes
J
Hebebrand
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D015992:Body Mass Index; D000067879:CELF1 Protein; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012307:Risk Factors
D000067879:CELF1 Protein; C102843:CELF1 protein, human; D016601:RNA-Binding Proteins
cross-disorder; dementia; loci; obesity; shared