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Recent insights into the molecular genetics of dementia.

ABSTRACT: Our understanding of the molecular genetic basis of two common neurodegenerative dementias, Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), has greatly advanced in recent years. Progranulin mutations were identified as a major cause of FTLD and a potential susceptibility factor for other forms of dementia. In addition, through copy-number analyses of previously identified disease genes and the study of microRNA regulation in dementia, new evidence emerged to support the view that subtle variability in the expression of known disease proteins could increase the risk for sporadic forms of dementia. Finally, in late-onset AD populations, the first genome-wide association studies were performed and novel potential AD susceptibility genes reported. These exciting findings provide novel insights into the disease mechanisms underlying dementia and hold promise for the development of potential treatments.

SUBMITTER: Rademakers R

PROVIDER: S-EPMC2864783 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Recent insights into the molecular genetics of dementia.

Rademakers Rosa R Rovelet-Lecrux Anne A

Trends in neurosciences 20090727 8

Our understanding of the molecular genetic basis of two common neurodegenerative dementias, Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), has greatly advanced in recent years. Progranulin mutations were identified as a major cause of FTLD and a potential susceptibility factor for other forms of dementia. In addition, through copy-number analyses of previously identified disease genes and the study of microRNA regulation in dementia, new evidence emerged to support the vi ...[more]

PMID: 19640594

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Project description:Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.

Dataset Information

Recent insights into the molecular genetics of dementia.

Publications

Recent insights into the molecular genetics of dementia.

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