Genome-wide association study of cognitive status and decline in the Amish.

Disorders of cognition are important from both personal and public health perspectives. The Modified Mini-Mental State (3MS) examination is a brief mental status test designed to detect cognitive impairment and widely used as a screening test for dementia including Alzheimer's disease (AD). The Old Order Amish have a homogeneous lifestyle with similar years of formal education, reducing the effect of confounding environmental factors for genetic studies. We carried out a genome-wide association study (GWAS) of 3MS score as a measurement of cognitive function in the Mid-Western Amish.After extensive QC, 1,873 subjects with both 3MS score and single nucleotide variant (SNV) data from Illumina chipsets were analyzed. The education adjusted 3MS score at baseline was used with age at exam, sex, and the first two values from principal components analysis in related samples as covariates. The annual rate of 3MS score change from 1st to 2nd exam was used as the measurement of cognitive decline. 933 people with available follow-up data were used with an additional covariate, baseline 3MS score. A linear mixed model was used to test for association.For the cognitive decline with rate of 3MS score change, LHPP gene on chromosome 10 was genome-wide significance (p=6.4×10-9 ). There were 6 more loci with suggestive associations (TMEM182; p=2.5×10-6 , NFIB; p=3.7×10-6 , HRAT17; p=4.0×10-6 , CDH13; p=5.1×10-6 , SDK1; p=5.7×10-6 , CECR2; p=6.6×10-6 ). For the baseline 3MS measurement, no SNPs reached genome-wide significance. However, we identified 5 loci with suggestive associations. They are either in known protein coding genes or regulatory region variants (TMEM229B; p=2.1×10-7 , TMEM178B; p=2.6×10-7 , CSMD1; p=1.0×10-6 , MTCO1P57; p=5.9×10-6 , LINC02122; p=8.9×10-6 ).We identified one genome-wide significant and 6 suggestive loci for the cognitive decline along with 5 more loci potentially associated with the cognitive status measured by 3MS score. LHPP is a protein coding gene that is overexpressed in the brain, associated with brain activity in Major Depression Disorder, and involved in a regulation pathway of cancer cells. In a previous study screening chromosome 10 for late-onset Alzheimer disease (LOAD), LHPP was one of the genes selected for putative functional mutation.