Stancakova, A. | bioRxiv Science

bioRxiv2018

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

genetics↗

bioRxiv2017

Heterozygous RFX6 protein truncating variants cause Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance

Finding new genetic causes of monogenic diabetes can help to understand development and function of the human pancreas. We aimed to find novel protein-truncating variants causing Maturity-Onset Diabetes of the Young (MODY), a subtype of monogenic diabetes. We used a combination of next-generation sequencing of MODY cases with unknown aetiology along with comparisons to the ExAC database to identify new MODY genes. In the discovery cohort of 36 European patients, we identified two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants were enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio, OR=131, P=lxl0-4). We found similar results in non-Finnish European (n=348, OR=43, P=5xl0-5) and Finnish (n=80, OR=22, P=1xl0-6) replication cohorts. The overall meta-analysis OR was 34 (P=lxl0-16). RFX6 heterozygotes had reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27%, 70% and 55% at 25 years of age, respectively). The hyperglycaemia resulted from beta-cell dysfunction and was associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

genetics↗