Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS ( P < 1 × 10 -5 ) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10 -8 ), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10 -9 ) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10 -8 ). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L , and CDC42 / WNT4 . We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42 / WNT4 locus ( P = 1.76 × 10 -24 ). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina ( P = 4.6 × 10 -8 ), OBFC1 in esophageal mucosa ( P = 8.7 × 10 -8 ), NUDT13 in multiple tissues including subcutaneous adipose tissue ( P = 3.3 × 10 -6 ), and HEATR3 in skeletal muscle tissue ( P = 5.8 × 10 -6 ) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization an...

In contrast to the rest of the genome, the Y chromosome is restricted to males and lacks recombination. As a result, Y chromosomes are unable to respond efficiently to selection, and newly formed Y chromosomes degenerate until few genes remain. The rapid loss of genes from newly formed Y chromosomes has been well studied, but gene loss from highly degenerate Y chromosomes has only recently received attention. Here, we identify and characterize a Y to autosome duplication of the male fertility gene kl-5 that occurred during the evolution of the testacea group species of Drosophila. The duplication was likely DNA based, as other Y-linked genes remain on the Y chromosome, the locations of introns are conserved, and expression analyses suggest that regulatory elements remain linked. Genetic mapping reveals that the autosomal copy of kl-5 resides on the dot chromosome, a tiny autosome with strongly suppressed recombination. Molecular evolutionary analyses show that autosomal copies of kl-5 have reduced polymorphism and little recombination. Importantly, the rate of protein evolution of kl-5 has increased significantly in lineages where it is on the dot versus Y linked. Further analyses suggest this pattern is a consequence of relaxed purifying selection, rather than adaptive evolution. Thus, although the initial fixation of the kl-5 duplication may have been advantageous, slightly deleterious mutations have accumulated in the dot-linked copies of kl-5 faster than in the Y-linked copies. Because the dot chromosome contains seven times more genes than the Y and is exposed to selection in both males and females, these results suggest that the dot suffers the deleterious effects of genetic linkage to more selective targets compared with the Y chromosome. Thus, a highly degenerate Y chromosome may not be the worst environment in the genome, as is generally thought, but may in fact be protected from the accumulation of deleterious mutations relative to other nonrecombining regions that contain more genes.

It is unclear if genetic variants affect smoking cessation treatment response. This study tested whether variants in the cholinergic receptor nicotinic alpha 5 subunit (CHRNA5) predict response to smoking cessation medication by directly comparing the two most effective smoking cessation pharmacotherapies. In this genotype-stratified randomized, double-blind, placebo-controlled clinical trial (May 2015-August 2019 in St Louis, Missouri), smokers were randomized by genotype in blocks of six (1:1:1 ratio) to three conditions: 12 weeks of placebo (n = 273), combination nicotine patch and lozenge (combination nicotine replacement therapy, cNRT, n = 275), or varenicline (n = 274). All participants received counseling and were followed for 12 months. The primary end point was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT, week 12). Trial registration and eligibility criteria are on clinicaltrials.gov (https:// clini caltr ials.gov/) (NCT02351167). We conducted the genetic analyses separately for 516 European ancestry (EA) smokers and 306 non-EA smokers (including 270 African American smokers). In African American smokers, there was a genotype-by-treatment interaction for EOT abstinence (χ 2 = 10.7, degrees of freedom = 2. P = 0.0049): specifically, cNRT was more effective in smokers with rs16969968 GG genotype than was placebo, while varenicline was more effective in smokers of GA/AA genotypes. In EA ancestry smokers, there was no significant genotype-by-treatment interaction. In the whole sample, although both were effective at EOT, only varenicline, and not cNRT, was significantly effective relative to placebo at 6-month follow-up. Importantly, this study suggests that genetic information can further enhance smoking cessation treatment effectiveness.