👤 F Cucca

Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K Show less

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. Show less

Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code. Show less

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. Show less