Landmark Papers

In collaboration with colleagues across national and international consortia, and/or drawing on data from his work with the Amish community, Dr. Haines, and his lab members have made significant breakthroughs over the years into the genetic architecture of neurodegenerative and ocular diseases. These contributions have been fundamental in worldwide research into the genetics of conditions that touch millions of lives each year.    

Below are some of the most influential papers that Dr. Haines, his lab team, and his colleagues have authored.   

Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A. (1993) “Gene dose of Apolipoprotein E4 and the risk of Alzheimer’s disease in late onset families.” Science. 261:921–923. PMID: 8346443

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer’s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

Corder, E.H., Saunders, A.M., Risch, N.J., Strittmatter, W.J., et al., Haines, J.L., Pericak-Vance, M.A. (1994) “Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer’s disease.” Nat Genet. 7:180–184. PMID: 7920638

Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

Haines, J.L., Hauser, M.A., Schmidt, S., Scott, W.K., et al. (2005) “Complement factor H variant increases the risk of Age-related Macular Degeneration.” Science. 308:419–421. PMID: 15761120

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately 43% of AMD in older adults.

Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, et al. (2007) “Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.” Nat Genet. Sep;39(9):1083-91. PMID: 17660817

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.

International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, et al., Pericak-Vance MA, Haines JL. (2007) “Risk alleles for multiple sclerosis identified by a genomewide study.” N Engl J Med. 357(9):851-62. PMID: 17660530

We conducted a genome wide association study to identify alleles associated with the risk of multiple sclerosis.  A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1×10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96×10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94×10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94×10(-81)).

Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

Fritsche LG, Igl, W, Bailey JN, Grassmann F, Sengupta S, et al. (2016) “A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.” Nat Genet. 48(2):134-43. PMID: 26691988

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Cukier HN, Kunkle BW, Vardarajan BN, Rolati S, Hamilton-Nelson KL, … Haines JL, Pericak-Vance MA; Alzheimer’s Disease Genetics Consortium. (2016) “ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.” Neurol Genet. 2(3):e79. PMID: 27231719

This study identifies a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.  Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.  The ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Bailey JN, Loomis SJ, Kang JH, … Haines, JL, Wiggs, JL. (2016) “Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.”  Nat Genet. 48(2):189-194. PMID: 26752265

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Rajabli F, Feliciano BE, Celis K, … Haines, JL …. Pericak-Vance MA.  (2018) “Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.”  PLoS Genet. 14(12): e1007791.  PMID: 30517106

 The risk conferred by ApoE ε4 differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations.

We analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population. Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

Kunkle BW, Grenier-Boley B, Sims R, … Haines, JL, … et al. (2019) “Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing” [published correction appears in Nat Genet. 51(9):1423-1424]. Nat Genet. 51(3):414-430. PMID: 30820047

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


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