Neil Risch

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Neil Risch

Neil Risch is an American human geneticist and professor at the University of California, San Francisco (UCSF). Risch is the Lamond Family Foundation Distinguished Professor in Human Genetics, Founding Director of the Institute for Human Genetics, and Professor of Epidemiology and Biostatistics at UCSF. He specializes in statistical genetics, genetic epidemiology and population genetics.

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Risch received undergraduate training in mathematics at the California Institute of Technology (1972) and his PhD in biomathematics at UCLA (1979). Prior to his position at UCSF, he held professorial positions at Columbia University, Yale University and Stanford University. He has been referred to as "the statistical geneticist of our time." [1]

Known for his work on numerous genetic diseases including torsion dystonia, Risch emphasizes the links between population genetics and clinical application, believing that understanding human population history and disease susceptibility go hand in hand. [2]

Population genetics

Risch has conducted significant work on the nature of human differences on a geographical scale. For instance, he used social and genetic data to analyse genetic admixture from White, African, and Native American ancestry in Puerto Rico, as well as relating this to geographical variation in social status. [3]

Risch considers that genetic drift is a more compelling explanation for the carrier frequency of lysosomal storage diseases in Ashkenazi Jews than heterozygote advantage, in light of analysis of the results of recent genetic testing by his collaborators and himself. [4]

After mapping torsion dystonia by linkage disequilibrium (LD) analysis he found it was genetically dominant and was a founder mutation. Other work has focused on the genetic basis of Parkinson's disease, hemochromatosis, multiple sclerosis, diabetes, autism, epilepsy and hypertension.

Group structure

Risch has worked on the genetic structure of human groups, for instance multiple levels of structure above the level of the individual increasing in scale up to the level of race. He has translated these results into theoretical impacts on, for instance, rate of decay of linkage disequilibrium, and practical application in personalised medicine. For instance, using the Framingham data, he showed that population stratification leads not only to fewer heterozygotes than predicted from Hardy–Weinberg equilibrium but also to spouses sharing genotypes at all ancestrally informative markers, accounted for by ancestry-related assortative mating in the previous generation. [5]

Psychiatric disease

In a small twin study on Autism (around 50 twin pairs for each disease and zygosity), he argued these disorders may be less heritable than previously considered, implicating a significant family-level environment effect. [6] Similar findings were observed in family studies [7]

Homosexuality

Risch has been a prominent critic of studies on the role of genetics in sexual orientation. [8] In 1999, with colleagues he published a sib-pair study that failed to replicate a previously observed linkage [9] between male sexual orientation and Xq28 DNA markers. [10] While an independent study also found evidence at the same Xq28 location, [11] more recent very large studies failed to produce any evidence of a genetic effect in this region of the X chromosome. [12] Risch also discussed ethical issues underlying studies of socially significant traits and the under-representation of minority scientists in human genetics in his 2015 ASHG Presidential Address, [13] which received a standing ovation. [14]

Genome-wide Association Studies

With his colleague Kathleen Merikangas, Risch is possibly best known for introducing the concept of genome-wide association studies for the discovery and characterization of genetic variants of modest effects underlying complex diseases. [15] That insight revolutionized the field of human genetics, leading to a large number of genome-wide association studies and the discovery of thousands of genetic variants underlying a broad range of diseases and traits.

Risch is also known, with his colleague Catherine Schaefer, for pioneering the linkage of genome-wide genotype data to electronic health records in a large health provider database (at Kaiser Permanente Northern California), which also demonstrated the power of genome-wide association studies on a large scale. [16]

Awards

Risch has received numerous awards and recognition for his scholarship. He is an elected fellow of the American Association for the Advancement of Science (2010), the California Academy of Science (2011), and a member of the National Academy of Medicine (2010). He was the 2015 President of the American Society of Human Genetics, the 2004 recipient of the Curt Stern Award (now the Scientific Achievement Award) from the American Society of Human Genetics and the 2023 recipient of the Lifetime Achievement Award (formerly the William Allan Award) from the American Society of Human Genetics, to date the only individual to have received both. He was also the 2022 recipient of the Paul Hoch Award from the American Psychopathological Association.

Related Research Articles

<span class="mw-page-title-main">Biology and sexual orientation</span> Field of sexual orientation research

The relationship between biology and sexual orientation is a subject of on-going research. While scientists do not know the exact cause of sexual orientation, they theorize that it is caused by a complex interplay of genetic, hormonal, and environmental influences. However, evidence is weak for hypotheses that the post-natal social environment impacts sexual orientation, especially for males.

<span class="mw-page-title-main">Identity by descent</span> Identical nucleotide sequence due to inheritance without recombination from a common ancestor

A DNA segment is identical by state (IBS) in two or more individuals if they have identical nucleotide sequences in this segment. An IBS segment is identical by descent (IBD) in two or more individuals if they have inherited it from a common ancestor without recombination, that is, the segment has the same ancestral origin in these individuals. DNA segments that are IBD are IBS per definition, but segments that are not IBD can still be IBS due to the same mutations in different individuals or recombinations that do not alter the segment.

<span class="mw-page-title-main">Dean Hamer</span> American geneticist (born 1951)

Dean Hamer is an American geneticist, author, and filmmaker. He is known for his research on the role of genetics in sexual orientation and for a series of popular books and films that have changed scientific and public understandings and perceptions of human sexuality and gender.

<span class="mw-page-title-main">Gene–environment interaction</span> Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

<span class="mw-page-title-main">Heritability of autism</span>

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.

<span class="mw-page-title-main">Medical genetics</span> Medicine focused on hereditary disorders

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

<span class="mw-page-title-main">Ancestry-informative marker</span>

In population genetics, an ancestry-informative marker (AIM) is a single-nucleotide polymorphism that exhibits substantially different frequencies between different populations. A set of many AIMs can be used to estimate the proportion of ancestry of an individual derived from each population.

<span class="mw-page-title-main">Human genetic variation</span> Genetic diversity in human populations

Human genetic variation is the genetic differences in and among populations. There may be multiple variants of any given gene in the human population (alleles), a situation called polymorphism.

In molecular biology, SNP array is a type of DNA microarray which is used to detect polymorphisms within a population. A single nucleotide polymorphism (SNP), a variation at a single site in DNA, is the most frequent type of variation in the genome. Around 335 million SNPs have been identified in the human genome, 15 million of which are present at frequencies of 1% or higher across different populations worldwide.

Xq28 is a chromosome band and genetic marker situated at the tip of the X chromosome which has been studied since at least 1980. The band contains three distinct regions, totaling about 8 Mbp of genetic information. The marker came to the public eye in 1993 when studies by Dean Hamer and others indicated a link between the Xq28 marker and male sexual orientation.

<span class="mw-page-title-main">Genome-wide association study</span> Study of genetic variants in different individuals

In genomics, a genome-wide association study, is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major human diseases, but can equally be applied to any other genetic variants and any other organisms.

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Genetic epidemiology is the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors. Genetic epidemiology seeks to derive a statistical and quantitative analysis of how genetics work in large groups.

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Genomic structural variation is the variation in structure of an organism's chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. Originally, a structure variation affects a sequence length about 1kb to 3Mb, which is larger than SNPs and smaller than chromosome abnormality. However, the operational range of structural variants has widened to include events > 50bp. The definition of structural variation does not imply anything about frequency or phenotypical effects. Many structural variants are associated with genetic diseases, however many are not. Recent research about SVs indicates that SVs are more difficult to detect than SNPs. Approximately 13% of the human genome is defined as structurally variant in the normal population, and there are at least 240 genes that exist as homozygous deletion polymorphisms in human populations, suggesting these genes are dispensable in humans. Rapidly accumulating evidence indicates that structural variations can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

<span class="mw-page-title-main">Complex traits</span>

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References

  1. ↑ Gitschier, Jane (2005-07-25). "The Whole Side of It—An Interview with Neil Risch". PLOS Genetics. 1 (1): e14. doi: 10.1371/journal.pgen.0010014 . ISSN   1553-7404. PMC   1183530 . PMID   17411332.
  2. ↑ Risch et al. 2002
  3. ↑ Via, Marc; Gignoux, Christopher R.; Roth, Lindsey A.; Fejerman, Laura; Galanter, Joshua; Choudhry, Shweta; Toro-Labrador, Gladys; Viera-Vera, Jorge; Oleksyk, Taras K.; Beckman, Kenneth; Ziv, Elad; Risch, Neil; Burchard, Esteban González; Martínez-Cruzado, Juan Carlos (2011). "History Shaped the Geographic Distribution of Genomic Admixture on the Island of Puerto Rico". PLOS ONE. 6 (1): e16513. Bibcode:2011PLoSO...616513V. doi: 10.1371/journal.pone.0016513 . PMC   3031579 . PMID   21304981.
  4. ↑ Risch N, Tang H, Katzenstein H, Ekstein J (2003). "Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection". American Journal of Human Genetics. 72 (4): 812–822. doi:10.1086/373882. PMC   1180346 . PMID   12612865.
  5. ↑ Sebro, Ronnie; Hoffman, Thomas J.; Lange, Christoph; Rogus, John J.; Risch, Neil J. (2010). "Testing for non-random mating: Evidence for ancestry-related assortative mating in the Framingham heart study". Genetic Epidemiology. 34 (7): 674–679. doi:10.1002/gepi.20528. PMC   3775670 . PMID   20842694.
  6. ↑ Hallmayer, Joachim; Cleveland, S.; Torres, A.; Phillips, J.; Cohen, B.; Torigoe, T.; Miller, J.; Fedele, A.; Collins, J.; Smith, K.; Lotspeich, L.; Croen, L. A.; Ozonoff, S.; Lajonchere, C.; Grether, J. K.; Risch, N. (2011). "Genetic Heritability and Shared Environmental Factors Among Twin Pairs with Autism". Archives of General Psychiatry. 68 (11): 1095–102. doi:10.1001/archgenpsychiatry.2011.76. PMC   4440679 . PMID   21727249.
  7. ↑ Risch, Neil; Hoffmann, Thomas J.; Anderson, Meredith; Croen, Lisa A.; Grether, Judith K.; Windham, Gayle C. (November 2014). "Familial Recurrence of Autism Spectrum Disorder: Evaluating Genetic and Environmental Contributions". American Journal of Psychiatry. 171 (11): 1206–1213. doi:10.1176/appi.ajp.2014.13101359. ISSN   0002-953X. PMID   24969362.
  8. ↑ Risch, Neil; Squires-Wheeler, Elizabeth; Keats, Bronya J. B. (1993-12-24). "Male Sexual Orientation and Genetic Evidence". Science. 262 (5142): 2063–2065. Bibcode:1993Sci...262.2063R. doi:10.1126/science.8266107. ISSN   0036-8075. PMID   8266107.
  9. ↑ Hamer, D.; Hu, S; Magnuson, V.; Hu, N; Pattatucci, A. (1993). "A linkage between DNA markers on the X chromosome and male sexual orientation". Science. 261 (5119): 321–7. Bibcode:1993Sci...261..321H. doi:10.1126/science.8332896. PMID   8332896.
  10. ↑ Rice G, Anderson C, Risch N, Ebers G (April 1999). "Male homosexuality: absence of linkage to microsatellite markers at Xq28". Science. 284 (5414): 665–7. Bibcode:1999Sci...284..665R. doi:10.1126/science.284.5414.665. PMID   10213693.
  11. ↑ Sanders, A. R.; Martin, E. R.; Beecham, G. W.; Guo, S; Dawood, K; Rieger, G; Badner, J. A.; Gershon, E. S.; Krishnappa, R. S.; Kolundzija, A. B.; Duan, J; Gejman, P. V.; Bailey, J. M. (2015). "Genome-wide scan demonstrates significant linkage for male sexual orientation". Psychological Medicine. 45 (7): 1379–88. doi:10.1017/S0033291714002451. PMID   25399360. S2CID   4027333.
  12. ↑ Ganna, Andrea; Verweij, Karin J. H.; Nivard, Michel G.; Maier, Robert; Wedow, Robbee; Busch, Alexander S.; Abdellaoui, Abdel; Guo, Shengru; Sathirapongsasuti, J. Fah; 23andMe Research Team; Lichtenstein, Paul; Lundström, Sebastian; Långström, Niklas; Auton, Adam; Harris, Kathleen Mullan (2019-08-30). "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior". Science. 365 (6456). doi:10.1126/science.aat7693. ISSN   0036-8075. PMC   7082777 . PMID   31467194.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  13. ↑ "ASHG 2015 Annual Meeting".
  14. ↑ Pham, Xuan (2015-10-23). "Highlights from the 2015 American Society of Human Genetics Conference | Biomedical Odyssey" . Retrieved 2024-01-11.
  15. ↑ Risch, Neil; Merikangas, Kathleen (1996-09-13). "The Future of Genetic Studies of Complex Human Diseases". Science. 273 (5281): 1516–1517. Bibcode:1996Sci...273.1516R. doi:10.1126/science.273.5281.1516. ISSN   0036-8075. PMID   8801636. S2CID   5228523.
  16. ↑ Kvale, Mark N; Hesselson, Stephanie; Hoffmann, Thomas J; Cao, Yang; Chan, David; Connell, Sheryl; Croen, Lisa A; Dispensa, Brad P; Eshragh, Jasmin; Finn, Andrea; Gollub, Jeremy; Iribarren, Carlos; Jorgenson, Eric; Kushi, Lawrence H; Lao, Richard (2015-08-01). "Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort". Genetics. 200 (4): 1051–1060. doi:10.1534/genetics.115.178905. ISSN   1943-2631. PMC   4574249 . PMID   26092718.
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