Yun Freudenberg-Hua

Genetic Variation in the Human Androgen Receptor Gene Is the Major Determinant of Common Early-Onset Androgenetic Alopecia

Androgenetic alopecia (AGA), or male-pattern baldness, is the most common form of hair loss. Its pathogenesis is androgen dependent, and genetic predisposition is the major requirement for the phenotype. We demonstrate that genetic variability in the androgen receptor gene (AR) is the cardinal prerequisite for the development of early-onset AGA, with an etiological fraction of 0.46. The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect. The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.

Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease

A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntingtons disease (HD). The expanded repeat length is inversely correlated with the age-at-onset (AAO), however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.

A family-based and case–control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder

A family-based and case–control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder

Systematic investigation of genetic variability in 111 human genes—implications for studying variable drug response

In order to identify single-nucleotide polymorphisms (SNPs) and analyze their characteristics in a set of 111 genes, we resequenced exons and flanking regions in an average of 170 chromosomes from individuals of European origin. Genetic variability was decreased in noncoding regions highly conserved between human and rodents, indicating functional relevance of these regions. Furthermore, diversity of coding nonsynonymous SNPs was found lower in regions encoding a known protein sequence motif. SNPs predicted to be of functional significance were more common amongst rare variants. Despite the significant recent growth of SNP numbers in public SNP databases, only a small fraction of these rare variants is represented. This may be relevant in the investigation of the genetic causes of severe side effects, for which rare variants are plausible candidates. Estimation of htSNPs reduces the genotyping effort required in capturing common haplotypes, for certain genes, however, this accounts for only a small fraction of haplotype diversity.

A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci.

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajimas D-value for each sample. The results showed a smaller Tajimas D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajimas D in 2400 out of 100 000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human–rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.

Investigation of the functional variant c.-169T > C of the Fc receptor-like 3 (FCRL3) gene in alopecia areata

A functional variant in the Fc receptor‐like 3 (FCRL3) gene has been implicated in susceptibility to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. Investigating a large case‐control sample of patients with alopecia areata (AA), we found no evidence for the involvement of FCRL3 in susceptibility to AA.

INCREASED BURDEN OF RARE LOSS-OF-FUNCTION VARIANTS IN ALZHEIMER’S DISEASE PATIENTS COMPARED TO CENTENARIANS

P3-118 INCREASED BURDEN OF RARE LOSS-OFFUNCTION VARIANTS IN ALZHEIMER’S DISEASE PATIENTS COMPARED TO CENTENARIANS Yun Freudenberg-Hua, Wentian Li, Danny Ben-Avraham, Jeremy Koppel, Soren Germer, Robert Darnell, Nir Barzilai, Jan Freudenberg, Gil Atzmon, Peter Davies, Feinstein Institute of Medical Research, Manhasset, NY, USA; FIMR, Manhasset, NY, USA; Albert Einstein College of Medicine, Bronx, NY, USA; NYGC, New York, NY, USA; Feinstein Institute for Medical Research Northwell Health, Manhasset, NY, USA. Contact e-mail: yfreuden@northwell.edu

Testing the genomic enrichment of a large copy number variation within schizophrenia linkage regions.

We hypothesize that copy number variants (CNVs) contribute to the location of schizophrenia linkage regions. Therefore, we test whether CNVs published by the International Schizophrenia Consortium are enriched in schizophrenia linkage regions recorded in the Online Mendelian Inheritance in Man database. For each region, the number of overlapping CNV events and the number of CNV base pairs are compared with 10 000 random regions of matched size. This shows an enrichment of CNV events within the linkage regions SCZD4 (22q11), SCZD10 (15q13-q14) and SCZD12 (1p36) for both cases and controls. The magnitude of this genomic enrichment of CNV event is more pronounced among cases for SCZD10 and SCZD12, whereas the number of CNV base pairs is greater among cases for SCZD4 and SCZD10. These results are consistent with a higher mutability that has produced an increased CNV burden in these regions in both cases and controls, with CNVs being more likely to be deleterious among cases.